Brain Cell Replacement to Beat Aging |Jean M. Hebert, Albert Einstein School of Medicine
8:13AM Mar 24, +0000
Speakers:
Joe
Creon
Larry
Vadim
Karl
Marty
Brian
Keywords:
cells
tissue
neocortex
aging
brain
grafted
function
neurons
replacement
people
plasticity
question
replace
alzheimer
important
moved
damage
graphs
organs
humans
I'm super excited to welcome john back here today. And he is from the other essence School of Medicine. And today we will be discussing brain cell replacement as the cornerstone to beating aging. So it's quite a mouthful, I think. Also Fun fact, we are currently considering riverbeds project for our health extension accelerator later this year. And I'm telling you this in case eight, you could be interested in mentoring or in supporting this project in any way, but also be in case you think that your project could potentially benefit from mentorship in this group, please apply to the accelerator. And I'm going to share the link here
by the chat. And with that, without further ado, I bet. Welcome. Thank you so much for joining. I'm terribly excited for the presentations. He's gonna present for about 25 minutes or so. And then we'll do questions. So please feel free to collect them already in the chat. All right, let's go.
Great. Thanks for having me, Allison. And for introducing me. It's wonderful to have this opportunity to share what we've been working on. Let's see. Now if I can share my screen, I have a few. They're all very simple slides, I hope related to the work we're doing with the rather bold title brain tissue replacement as the cornerstone to beating aging. And I'm putting this forth as an idea for discussion, I'm going to try to convince you that that's the case. Whether or not you agree with me, in the end, it would be great to discuss why or why not? Let's start maybe with something that they see I put it in screen mode. Okay. You can see my slides, right. Okay, let's, let's start with something that I think we all agree on. And that's, you know, we want to achieve health. And the longer we can be healthy and live longer, the better. I think we all agree that diseases get in the way of this. And the greatest cause of diseases and mortality is aging. And also aging even on its own. So if you're lucky enough to be diseased, flee and make it to 100 years, you're still going to be quite frail, and, you know, might be considered healthy for 100 year old. But if you compare yourself to 20 or 30 year old, you're not going to be quite so healthy in any way. So I think where there's a lot more room for discussion of ideas is, how are we going to be aging, and this is where I'm going to try to
I can't advance anymore. That's when I try to see if I can restart things. That's never happened to me before.
And it's funny because it also doesn't happen in the in the test runs. Yeah. Okay. Perfect. Move on the slide again. Yeah, we're
on the slide, but it won't move forward. So let me just try maybe I can't even escape the slide. I've lost all control, I guess. Okay, let's
just the right arrow at the bottom of the screen advance it.
Try it out. Right. Okay. Well,
I think while we're waiting and john bad, you just interrupt me. Yes. Okay. Good.
Thank you, whoever that okay. So where there's more room for discussion and ideas, I think is how we're going to defeat aging. And this is not a new idea. Tissue replacement by tissue replacement. I mean, cells, tissues, organs. replacements are have conceptually been around as an idea to be aging for a long time. But I want to try to convince you that you know, the time is right. And also, if tissue replacements ever going to be useful, we need to figure out how to replace the brain as well. Not as a whole organ, but you'll see it shouldn't be doable. Okay. So the first thing I want to start with is a question what is aging? And that might seem like a rather simple question, and forgive me because to a group like you, you know, what is aging? I think we would all think we know what aging is, but I think it's worth bringing up because we often talk about the effects of aging like diseases or you know how different intracellular pathways are different functions are affected in aging. And I would think of those more as the effects of aging rather than aging itself. And so biologically speaking at its core, what aging is, and this is also been known for a very long time is the accumulation of damage to all our classes of macromolecules. So DNA, carbohydrates, lipids, proteins, and this damage is very complex. So if we look just at proteins themselves, as one example of the macromolecules that are affected by aging, there's many different forms of damage that have been documented to occur. You know, glycation, deep urination, oxidation, and the list goes on. This is just a partial example. And the same is true for DMA, carbohydrates and lipids very complex forms of damage. And we've heard about it pretty recently, in this forum, how these damage affects different intracellular pathways, many pathways and how to understand you know, how aging is affecting cells, there's a lot more basic research that's needed to identify pathways that we have yet to identify, that are affected by aging, and also how we might try to reset some of these pathways to function normally using combinations of drugs or pharmacological agents. But I think we need to acknowledge the limitations of that approach to tackling the effects of aging. One is that finding combinations of drugs that will reset these pathways, many of which are, you know, life sustaining pathways and delicate balance with each other, without causing more side effects than benefits, I think, for me, at least, it's hard to imagine, given that we have trouble often finding a drug for a simple ailment that doesn't have side effects. And also, you know, all it takes is one essential pathway to be malfunctioning to get effects such as accelerated aging, like you see in Hutchinson Gilford or in Lerner syndrome. And, you know, okay, so maybe my imagination is limited, maybe we can actually come up with these drugs, but even then, we won't be tackling the cause of aging itself, which is the accumulation of damage. And if we don't do that, then you know, we might be held might be able to live a little longer and healthier, but we won't be able to defeat aging.
So, okay. So to defeat aging, and I think what we need is a replacement approach. I think this is mandated by the complexity of the damage. Okay, so let's talk about replacements. So, you're the human body replacements per se, in terms of implementation are not problematic. So every part of the human body has been surgically replaced over the last few decades. And I mean, every part of the body, I was surprised to find out, you know, the face skull, you know, arms, of course, every internal organ, every part of the body sexual organs have been replaced. So surgically, the implementation is not necessarily problematic. I mean, no one likes surgery, but it's doable. The problem is, though, that many of those replacements have come from deceased donors. And, and in some cases, you know, artificial limbs and organs are far exceeded. So, what we need to get replacement to work as a general strategy is better lab grown organs. Right. So those have been in development for a while. We heard Sonia aaronson, in the first meeting, raised a very important question, what's happened to these organs? And the answer is, well, they're still in development, they're getting better and better. But progress is frustratingly slow. And a lot of that has to do with a lack of investment. In developing these organs. These organs are only developed to treat specific diseases right now. Not Not for aging, and the investments that go into that are rather limited. But eventually we'll be able to replace all the different parts of the body, except, of course, the brain as a whole org. So you know, if we can replace every part of the body, but we can't replace the brain that will leave us you know, in having a replacement for the rest of the body will be all for not if your brain is still degenerating and you're becoming senile, and you can't remember anything. So the brain needs to be addressed as well. And obviously, it can't be replaced as a whole organ. But it shouldn't be replaceable, based on what we know, and the evidence to date at a cellular or small tissue level, level, if we do it progressively over time. And I'll go into that in more detail because that's, that's more what my group focuses on. And we should be able to replace the brain progressively without losing who we are as individuals, right? That's important. And so the first reason why brain cell or tissue replacement makes sense, is that if we think of the brain or the human brain, which was the photo on the first slide I showed you, is mainly neocortex, right? That's the outer part of the brain that's all folded. That's what defines us. as a species. I mean, other mammals have the important cortex as well, but ours is disproportionately large compared to the rest of our body. It also defines us each as individuals, that's where our long term memories are stored, our thought patterns, our self identity. But so the neocortex is extremely plastic by nature. And we've known this for a long time from studies and in model animals. But my favorite example to illustrate how just how plastic the human neocortex is, is
this one, so in this case, what's happened to patients over the course of several years, is that their language Center has completely moved to New substrate without a disruption in their ability to speak. And they didn't notice any difference, and the people closest to them didn't notice any difference. So what happened in these patients is they had these slow growing benign gliomas, I hope you can see my cursor here. This is glioma right in the Language Center. And over the course of eight years, it's growing without being diagnosed, and no one can tell it's there. And then eventually, the patient has a really bad headache, or even a seizure, they go to the hospital, you know, bad news, you have a brain tumor, good news, it's operable, they take it out with surrounding tissue for good measure. And in most cases, the patients can still speak perfectly well. And these are not young, you know, like infant patients, these are adults of advanced ages 50s 60s. And during that time, their language has moved to a new part of the neocortex. Right? This doesn't happen when you get a stroke in the same area, that's a catastrophic event. And there's no time for plasticity to take place. So the idea that this has this transfer of function to a new substrate has to occur progressively over time, right? That's an important concept. But in any case, it does suggest that that replacing or providing young naive tissue should allow us to regenerate rejuvenate the neocortex in the brain, if we do it progressively over time. So the other reason why brain cell replacements or tissue makes sense, is more recent evidence over the course of, you know, five, or 10 years at most, where many labs have been putting in immature precursor cells for the neocortex in the adult neocortex. Ensuring that these immature precursors differentiate into neurons that make the appropriate connections to distant parts of the brain. In model animals, so not in humans, although there is one example although not in the neocortex in humans, in the in the ventral telencephalon. That also supports the idea that young neurons in the adult can still find their way to appropriate targets. And I just gave one example here. It's kind of my favorite from Faulkner at all. Munich. But there's been many examples from a dozen labs, independently finding the same thing. And I'll show you a little bit of data from our lab as well. Although I'm not showing it all. So the so the general idea, then, in doing progressive replacement of the neocortex would be as follows. So, here, you'll recognize a cross And sort of the human brain. And this outer layer here is the neocortex blown up, so you can see it a little better here. And keep in mind this very simplified cartoon. This is more of a conceptual cartoon, but in practice could be how we would execute progressive brain cells, brain tissue replacement. So first of all, the aging brain loses a lot of volume, creating space to put in new tissue. So assuming we could make neocortical tissue we could transplant it grafted in the neocortex. So we already lots of labs are already grafting a tissue, it's just not very functional yet. The idea is we would make it functional before grafting it, then we could silence to eventually get rid of the old tissue that's there, we could silence whoops, sorry. Neighboring parts of the neocortex. Like the small brain glioma did, of course, we would not use glioma as a means of silencing an area of the neocortex. We could do it pharmacologically, there's a lot of choice of jobs that the details would have to be worked out, of course, and then we could remove that once it's silenced, not used anymore. And the functions have moved to New locations, in particular, this naive substrate that's,
you know, ready to to encode any new function, then we can remove the the old brain tissue and progressively regenerate the neocortex in that way. So I'll just show you a couple of data slides from my lab. So this is what we've been working out in mice, we're using the adult mouse neocortex as a platform for rebuilding functional human neocortical tissue. Here's one of our graphs. So here's the lesion, we just make these canonical lesions in which we can insert cells that we have in scaffold. And these cells, when they include neuronal precursors, differentiate and send projections to normal targets along normal pathways, such as the corpus callosum, and targeting down to the striatum. So we have, we have a paper that's in bio archives, which describes this a little more detail. If you're interested. When we include vascular cells in these graphs, which is important to maintain the health and viability and function of these graphs, we find that these vascular cells form blood vessels, they fuse with the host vasculature here, the draft vessels are labeled with GFP and green, they fuse with the RAF vessels. And we can measure blood circulation within within them in live animals that have graphs using two photon microscopy. So you can see a little green dots moving by really fast, those are red blood cells that we labeled with dye oak, which is just a fluorescent dye. So so that's really good. That sounds good, right. But there's still a lot that needs to be done before these, this grafted tissue is functional. One thing that's missing is a lot of cell types. So what we've done so far is raft excited Tory projection neurons. Those are the principal neurons of the neocortex with vascular endothelial cells. And we see that they both integrate very well, but they can't possibly function normally, if they don't have these other cell types as well. So we want to start including those cell types in our graphs. And we know how to generate all these cell types from human embryonic stem cells. The protocols are improving the not always perfect with 100% yield, but they are getting much better. And they're certainly good enough to start testing in our in our models. So that our first aim from my lab is is to assemble these neocortical, all the cell types that we need to make a complete cortex shown here in our graphs, and it's not just putting them all in there, they have to be organized correctly, as well. There's a certain silo architecture that is needed for the proper connectivity of the neurons in the cortex shown here. So you can see the different layers have different neuronal densities with different neural identities or cell types. So we're using a scaffold, we're developing a scaffold to be able to do this. And so far, we've shown that our scaffold supports the survival differentiation and integration of both the neurons and the vascular cells, whether they're human or mouse cells. So So that's it. Start, is we still need to optimize it, there's still some issues with it. And equally important, and something that we want to do in parallel is, is to show a proof of principle that neocortical tissue replacement can work. Right. And the way we're doing that is, this is just an outline of the experiment. But we train an animal to do a particular task that requires, you know, multiple parts of the neocortex, but the information is eventually processed to control just, you know, the right for live digit, for example, and so that all the information that's processed has to go through there, that part of the neocortex, it's a small part of the motor cortex. And so what we do, what we want to do is lesion that part of the neocortex put in our graph,
and then confirm that the deficit in the ability to do do the task is there, which is not a problem. And then, in this graph, we also have these floating electrodes that we're testing out, that can monitor the activity of the precursor cells to tell us when the the graft has differentiated to the point where its neurons are becoming active. At that point, we re initiate behavioral training. And once the animal gets good enough to perform the task, again, we can silence specifically our grafted neurons, because we've infected them with a particular channel that we can silence the neurons with, to show that the animal can no longer perform the task and requires the function of those neurons to perform that task. Right. And so this is transient. So this is a drug activated channel, once that drug washes out, then the animals should be able to perform the attack task again. And we can redo this several times. Right. And that would be the first demonstration that neocortical replacement is possible, right? Because we will have replaced the piece of neocortex with new tissue that has taken on the loss function, and provides a useful behavior to the animal. This has not been shown yet. So I think it's an important landmark experiment. People have put in a lot of cells into the adult brain and shown that they have benefits. But those are from bystander effect. So it's just the fact that the cells secrete good factors and keep surrounding cells happier. No one I should have shown functional replacement of the neocortex. Yeah. And so that's why this aim, I think, is one that it's very important for us to do sooner rather than later to generate a lot of interest and investment in this approach. Okay, so I think, Oh, yeah, just a couple of slides on this. This is just what our floating electrodes look like, you know, there's a solid platform that is attached to the skull, and it has these smaller electrodes that are inserted into our graph. This is what it looks like, in reality, you can see here. So we've been preparing to do the actual experiment by by getting all our tools ready, our electrodes, and here's just the people who are we've been collaborating with at some level. But again, you know, it's art time by somebody in their lab contributing to this project. And what we really need to accelerate this moving forward is to have dedicated people, people that are 100%, dedicated to this project, from these different groups that specialize in the different aspects of this project, which we need in order to make functional neocortex. So I don't know if I've convinced you or not, whether in combination with replacements for other parts of the body, replacement of the brain, particularly the neocortex, you can talk about the rest of the brain as well. But particularly the neocortex, it can be the cornerstone to beating aging. So I don't know how much time I took. I can't.
All right. Thank you. Lovely. You're great on time. And I think I finished quite actionable. You're getting a lot of thumbs up, I think and so okay. We already have a few comments from in the chat. And perhaps, Christine, when you start with your question, and say maybe a word or two just about your background, so john has Hasn't hasn't context for your question. Thank you. Um,
I'm Christina, I'm the founder of fly cat, the other products we're working on making hypothalamus stem cells from humans. I think the watch are doing is absolutely amazing. And this is the way of the future. Do you think it's possible to engineer these cells that you're making so that they become refractory like resistant to all the inflammation and all the causes of aging that, you know that you can't really change the microenvironment. But maybe by engineering the cells and this touches on some of the comments, some of the other people have said, maybe by engineering the cells you can make the salsa factory to the environment?
Yeah, absolutely. I mean, because these cells, right, as you know, are grown in culture, you can modify them any way you want, right? And if we have the knowledge to make them better in any way, before grafting them, we certainly can. I assume we certainly would. You know, but yeah. Thank you. Thanks. And good luck with the hypothalamus. That's, of course, another essential part of the brain.
Thank you. And next up, we have Marty.
Oh, you're muted.
Sorry. I'm Marty Edelstein. I am one of the cofounders of covalent. And we develop a one molecule thick materials to use for water purification and renal replacement devices as part of a larger system. And my question, if I can find it again. Was do your constructs attract blood vessels? As they're coming in a scheme quickly? Initially?
Yeah, no, that's a very good question. So our, in our sample, we put a badge out, we put an h1 to encourage vascularization. And, you know, we were worried at first we were doing these graphs in sort of pristine, the A cortical tissue, as well, you know, what happens if we do it in damaged tissue? Is it going to be less able to vascularized incorporate, and we were pleasantly surprised to find it was the opposite. So our first paper in bio archive shows that we use stroke as a model in that case, which would also be our first clinical case study for this approach will be stroke, not aging. But in those mice, we find that vascularization is greatly improved by grafting into an ischemic environment. And we still get nice differentiation and projection and connections of our neurons
that's really, really consists. Sorry, go ahead. That's really consistent with old work we had done I when I was in college, actually. Oh, and read vascular rate revascularize ng ischemic baby rat kidneys. And it actually worked on human neonates? Oh, yeah. This is ages ago at Mass General, pediatric surgery department.
Did you know Did you ever figure out why like, what were the factors that promoted that?
No, no, we implanted pedicles into a scheme of kidneys, and then sack the rats. And look, the barium sulfate profusion to see where it was actually out of revascularisation was going over time. And you get complete revascularization. So you could do an effect to me on the other kidney, and then cut off the original blood supply to the original kids, the kidney that was left and kidney would function totally 100%.
So there may be something about damage and inflammation that activates
obviously signals going out. Thank you. All right,
let me I'm reading out kids question Keith is asking, Ron, is there any reason to believe that if a patient has advanced Alzheimer's for example, will newly grafted tissue serve to remediate such systems condition? Or will the newly grafted tissue quickly become similarly corrupted due to the surrounding environment? He's not expecting a definite answer, of course. Just curious if there's reason for optimism.
Yeah, so yeah, so exactly like Allison said, I think there is reason for optimism, we don't know. The reason. So there's a couple of points that might address that. One is we already have a lot of data for Parkinson's, right? So but that's a different part of the brain. That's the basal ganglia. And so, you know, the graphs of stem cells or fetal midbrain tissue were transplanted decades ago. And in postmortem tissue, they found that it takes, you know, at least 15 years, it but the cells are still there, the grafted cells are still there after two decades, but up till 15 years, they the grafted neurons don't show the deterioration that the host neurons have shown. So over time, yeah, they start showing it but you know, you're already getting 15 years there, of renewed function, there are problems with those other problems with those graphs that people are addressing. And there's several clinical trials now that are starting again, after grafting in that part of the brain. So the same thing might be true for Alzheimer's. But the other thing to keep in mind, too, that addresses this point is, is this inherent nature of the neocortex for plasticity, it is competing, our neocortex is always serving competition, so whenever we need it for whatever function we needed for, that's the function that wins out. So in, so in Alzheimer's, it's accelerated degeneration, there might be a little, you know, plasticity is challenged a little more than it would in an elderly person who is highly functional, right. But even in those highly functional, elderly people, if you look by MRI at how they're using their neocortex, for routine tasks, they use wider and wider areas of the neocortex to perform these tasks. And that's why they're able to appear to be, you know, high functioning, but that's very different than a young adult brain where the functions are much more compartmentalized and efficiently used, right. So, so that tells us that, you know, this level of plasticity and the competitive nature of the neocortex, if you put a tabula rasa structure in there, it will get us right. You know, whether it will or help quickly or not, it will succumb to whatever is causing Alzheimer's and the disease brain. You know, we'll have to see, but I guess, but I think there is reason to be optimistic that it will be effective for a while and, you know, if you can include what Christine was saying, you know, by then you have some idea of what was causing Alzheimer's, you can address that, so that it's not happening in these graphs as well.
So I think it's important to follow up with the pessimistic case here too, though, I, it seems very naive to blindly assume that you'll get however many decades that you would get from, you know, cells as as if they started the pathology of Alzheimer's or whatever. without, you know, we know that there's crosstalk between the different kinds of damage and the signal, you know, both signaling and other types of crosstalk. So, for example, the misfolded proteins that build up in various diseases, especially the neurodegenerative diseases, have a prion like virility to them. So simply putting in new tissue, you know, new new tissue, the misfolded proteins are likely to simply act you know, spread around to the new tissue and this the rate of that spread is probably, you know, at least as fast as the rate of the new training you know, as you said, it takes you know, years and years for the slow you know, change the shift in functionality to go from one part of the brain to the new tissue. So, this seems like a great and important component of an anti aging strategy that comes in you know, in a one two punch with actually getting rid of and clearing the existing damage but I would be very I wouldn't be too optimistic about this working by itself without actually fixing the underlying damage. In addition, it's sort of like the you know, the way people have talked about reprogramming and other kind of stem cell approaches to replace the tissue this looks looks great, but I think I think you're going to need you know, depends on which theory of Alzheimers you use, but you know, for exams, To the extent to which it CSF drainage that's being impaired, replacing tissue with grafts isn't going to solve that problem. And the pathological cascade seems to be such that once that gets very, very far along, then even brand new neurons and things would get affected very quickly.
Yeah, yeah. I mean, you bring up several important points there. And maybe working backwards. So one of them Yeah. Right. If it's a CSF problem, then, you know, just replacing neurons is not going to solve the problem. So of course, for it, you know, if you want to address aging, or maybe even also amazed, because Alzheimer's, if you ask 10 different people what Alzheimer's is, you get 10 different answers, right. So you don't only want to replace the neurons for even that tissue in the neocortex. But you'd also want to replace you know, the vascular Plexus of the BIA as well as the choroid plexus. So the other parts of the brains brain would also have to be addressed in a true rejuvenate, you know, in a final rejuvenation strategy. So, yeah, I agree with that, as far as, like, the aggregates, you know, I for the Alzheimer aggregates, you know, I don't know that the experiments ever really been done. Because, you know, the model systems are not great. And we can't do this and humans, to say how much those either intracellular or extracellular aggregates move or reseed other areas, right. So I don't know, maybe that could be a problem, but it's definitely something you know, one of the first things that we need to be looked at, in doing early clinical studies. Thank you.
Thanks. Lovely. Next one up, if Joe.
Ah, yeah.
So I'm, remain, I remain super excited about what you're working on. Thank you for working on it. Also, read your book The other day,
thank you great.
and bought a few copies for other folks as well. I'm wondering, it's obviously kind of a long, you'll take one, okay. It's obviously kind of a long term project. Like, it's doesn't feel like oh, you just make a company out of this, and just start delivering therapies to people. And in a short number of years, like this, a bunch of science to be done. So it feels like, you know, like, like a, like, a little like an institute or something like that. Or like, like, I like your, your, your impulse to get people working on it full time. And like, so for that you kind of want to get people out of their existing academic labs and into one focused environment where they can all drive.
That would be ideal, you know,
kind of drive the project in a focused way, all together, to clear out all the roadblocks and make everything go fast. Some kind of Institute like thing, and I'm just thinking about, like, how to fund that, who's gonna fund it? And
same question.
Yeah, so the, but the thing that came to mind would be if, if you could define a clear, sort of, like, like, motivating goal, like an overarching milestone of some kind.
Like,
we're gonna bring these people together, we're gonna, it's gonna take, you know, 12 scientists working for five years, and at the end of it, we're going to, we're going to achieve x, you define x in some way, like we have, you know, the entire neocortex of a mouse is replaced, and the mouse can then like, run around, do amaze, mate and have babies or whatever, like, whatever you're like Turing test for brain replacement is. But that could be that could be motivating.
Yeah, so we do have the development plan and willing to share learnings interested, I guess, with milestones, and yeah, it's sort of a, you know, fine, within five years, what we think we can accomplish, given that, you know, a group of people working on this,
how much would that cost?
Yeah, we've adjusted the anticipated cost anywhere from 10 to 1510 to
five zero or 10 to one, five,
and 10 million to five, zero. Got it. Okay?
somewhere in that range. Okay, thanks.
And you have such a milestone plan written out? Maybe you want to share it with me, so I can share with the group afterwards. Okay, and we have Larry next. Lawrence, are you here? Maybe you find it hard to mute.
I found the unmute button. I couldn't find the share button. But for some reason, I don't know why, you know, but raise my hand. But, um, yeah, I'm john, and I'm sure you've heard this before I work with the FDA. And you know what he does? You know, why don't you try spinal regeneration, where the function is Nolan and things like that, first off to see, but the plasticity of the spine doesn't seem to be that great in the spinal cord. And so when you're bidding on here is that there's a lot of plasticity in the neocortex, which there could be I mean, and I was just wondering how much you've done study of like tumors, where they've taken out where they know, they've destroyed areas of functionality. I mean, you showed one there. But you know, there's been a lot of mapping of the brain areas and things like that, where, you know, you, you know, you show where things are localized, and where things recover and things like that, then, you know, why, you know, I haven't seen, you know, good, consistent, you know, there's a lot of brain surgery, a lot of tumor removal, and there's a lot of recovery from some of the stuff like you said, people lose their speech, they regain it, you know, things like that, and even from strokes and stuff like that. And how much remapping Have you been, and the reason why you're focusing on the cortex is because the evidence of plasticity, why things like the spinal cord don't seem to have a lot of plasticity. I mean, they there's been a lot of efforts to regenerate spinal cords, and, you know, they, they get somewhere close with a mouse, they can kind of limp a little bit, or something, and then they, you know, why, like hands programming, or they think, like hands are involved in the cells sort of getting in the right place, but you know, is is that, is that why you think approaches? is some chance of doing something? Or? Or is there no place to see that doesn't matter?
No, I mean, plasticity is an integral part of it. And, and, yeah, so I mean, we're not, I'm not a neurosurgeon, we're working with neurosurgeons that do implants in humans as one of our collaborators. But my, one of my favorite neurosurgeons is this guy, for in Paris, who does a lot of these brain surgeries, to resect tumors and other brain surgeries. But to some extent, they all do this, right. So it's open brain, awake surgery. And so you know, they do a lot of mapping with electrodes to see, you know, where functions are, initially, you know, they always did this to avoid hitting important areas, with their with their scalpel. But, but in this case, they're doing it to see where things have moved, and even had patients with recurrent tumors, where they went back in and re mapped and showed that, in fact, you know, language have moved again to a different place, after a new tumor has grown over the course of years. So this is done a lot, a lot of this is done extensively, and also by functional MRI, of course.
So what would be the purpose of it, then if you already have this plasticity there? To do this? I mean, adding something that's, you know, where the capabilities are already there? What's the purpose of it? If it's not to read? You know, you know, can you tell that you actually recover functionality that was destroyed before, and it doesn't seem to be coming back.
I mean, the main purpose, again, is to, you know, in stroke, of course, it would be to give the opportunity for the person to more easily relearn whatever function was lost. But for aging, it's, it's to get rid of the, the brain, the neocortex, that you know, what your, that starts going downhill, even a
book you're going to replace with fetal tissue, or what kind of tissue Are you going to generate to replace the
stuff. So this is the tissue that we're engineering with all the cell types as well as the correct side of architecture. We could deal with Beto. And in fact, we do have a couple of experiments where we're testing using human fetal neocortical tissue in graphs, but that's, you know, and that might work, but it's not a very scalable approach, or applicable approach.
So these are going to be cell lines that you're going to you're going to, you're going to you have a group of cell lines, the glial cell line gf neural cell line jL macrophage or dentro?
Yeah.
We start with human embryonic stem cells.
Okay, so you start with that. Yeah.
And once we get to patient,
so I mean, if the actual scale is, you know, like, if you go back to Jesse's example, I think it was it was better than mine. To be honest.
If you go back one slide.
I think this is a different meeting.
I muted him. You go ahead, john. Oh,
yeah. So yeah, so we can get all the cells from human embryonic stem cells. And once we get to the clinics, and doing this with patients, we can do the same with induced pluripotent stem cells. Right. So we don't have to worry about rejection.
Okay, so you have human embryonic stem cell lines, and you see, differentiation that gives you something like a needle cortical tissue, then is what what you're seeing?
Well, yeah, so we have to reassemble the cells because the protocols right now, you get sort of purified, single cell types. So yeah, so you generate the single stem
cells, we have a difficult time defining what they are. I mean, you know, what are all the markers needed to call it a stem cell? I mean, stem cells are really different difficult for us, you know, mesenchymal, you got, you know, the you got the, you know, the blood stem cells, the neural stem cells are, you know, I mean, it's always difficult to know what markers really make it a stem cell, and things like that. And then when they're finding how to get functionality back.
Yeah. But we have a much more functional definition of the stem cells we use, they give, they generate the cell types that we want. Right, we will get that we're not looking to, you know, characterize this template
in a matrix like because you have wheel cells around nerve cells, you have, you know, things like that. It's not a simple, simple thing.
No, I mean, the, a lot of these precursors self organize, but but the principal neurons do not. And so those are the ones that we have to pay attention not just to the cell types, and their differentiation stage and the ratio and everything but also their position in.
Okay, no, no, I
think it's an interesting one thing to look at. Yeah. Yeah.
Thank you. Next one up, we have buddy.
Hi. Yeah, I worked at Brigham Women's Hospital, Harvard Medical School, just academic researcher. So this is a super interesting project, actually. My question is, because we study aging, how how do you think this would affect the grafting the cells would affect the biological age of the rest of the tissue of the brain? Because I guess this project has many similarities to like Coronavirus, so bone marrow transplantation from from young to old. And, you know, there's always a question that, yes, you fix a particular problem. And and maybe you rejuvenate a subset of the tissue, but then this young tissue that directs the old tissue in the, in the grafting procedure itself, might age the rest of the brain. So I wonder if you, you know, consider this kind of really looking at other parts of the brain and seeing maybe if there is a rejuvenation, but at the same time accelerated aging of the rest of the tissue, or not, at least to exclude that disability?
Yeah, yeah, no, those are very important points, right? The rest of the brain or even the recipe in the cortex, and how full tissue and young tissue are going to interact. So, you know, what I didn't include here, and as part of a longer term plan is, is to address the other parts of the brain. That's why I'm very excited to hear Christine working on, you know, hypothalamus root replacements. Because we need these replacements, not not the neocortex replacing it further, it's not going to fix the other parts of the brain are still gonna be old. I don't think it'll accelerate the aging of the other parts of the brain but certainly unlikely to greatly affect or rejuvenate them. So, you know, the different parts of the brain have to be addressed. And the way this would be done foreseeably is by doing, you know, functional replacements or auditory cortex with auditory thalamus, other auditory parts of the brain at one sort of unilaterally the other side, so, they develop together young and young parts of the brain and then both subcortical and cortical parts reveal to the better minutes how do we develop normally? This this handshake phenomena with the library neurons are going out to the cortex political I want to come down and contact each other. And connect. Maybe I'm meant meant just simply like apply the genie clock or someone that kind of blocks, you know, to these tissues. Just to simply test
what's going on.
Oh, yeah, yeah, no, I mean, yeah, well, I think that'll be a very important thing. thing to look at in our model organisms is how the graph, a young graph affects the old brain and how the old brain affects the young graph. Yeah. And for that, we can look at all different markers.
senescent cells would be good to look at too obviously, there's going to be Yeah, separating due to the graph procedure itself, for example.
Yeah, senescence cells, epigenetics, protein aggregates, like you mentioned before. All these things would be very important.
Thank you. I had Korean with a comment and then Brian.
I thanks, Alison. Um, okay. So I'm wondering if you are at all familiar with the work of Ellen Heber cats in Philadelphia, and who for quite a number of years now has been inducing regeneration in mammalian organ systems without grafts but merely by manipulating the metabolic environment. Well, first with knockout gene variants, but then by just with drugs. And I believe they've made progress not only in the heart and bone, and skin, but even in the CNS, I'm not sure about the brain. I know they've made progress in in spinal cord regeneration, again, without grafts. any knowledge of that any interest in that happy to follow up later? Or if you already know, maybe you have a comment?
Yeah, no, I'd be happy to follow up. But just make a quick question. So what do you mean by regeneration, so there's a damage that's induced, and then they apply these, these drugs are manipulations, to better promote regeneration.
Here's what they seem to have figured out. And this is my, you know, approximate understanding, having been her friend for quite some time. And she came to foresight, and presented, at least on one occasion, which Alison put a link to in the chat. And you might want to see it, because it's pretty cool now, but they did things like um, cryo, probing, and damaging the heart of a mouse that first had this knockout and the heart essentially, fully reject, they do ld 50 cryo damage to the heart. And then the mice that were damaged, grow back with hearts that are histologically undiscernible, from the healthy hearts of the control mice. They also then figured out they did this with other systems, bone Jaws, you know, full mammal organ systems, pretty much they've what they've determined is that the that the regeneration capabilities that we tend to think exists mostly in like amphibians and stuff like that are actually latent in mammals, but they're turned off. And so they can be turned back on, at least under certain circumstances to a certain level of efficacy, like it's not perfect, but it's damn good. And so maybe you can turn it on in the brain to do some of these things that you're doing with grafts. It kind of causes from what I understand by manipulating certain metabolic factors, which they first did with Gene knockouts. And then later on, they figured out just how to do it with drugs, they can set a metabolic environment for the cells that sort of promote instead of promotes scarring, it promotes differentiation, and then re differentiation to regrow an organ system like an amphibian does when you got off it's like, or something like that.
Right. Right. No, I mean, that. That's also an area I think, as from as well, because it's, it's very similar in a way, you know, you you're removing damaged tissue or good tissue if you're just doing a test, and then getting new tissue there. Right. So it's sort of should replace all forms of age related damage. In doing so, except maybe DNA mutations unless they're selected against in the growth phase of that organ. So I think, yeah, there's potential there too. And I look it up. I look forward to reading more about
Yeah, look at that thing that Allison posted in the chat. on that link, it's
pretty good to connect you to afterwards.
I might, you know, another thing I just want to mention here, and then I'll stop is that this might be this just occurred to me recently. Maybe this is an example of this, of this sort of combination of sort of Dave Sinclair's methylation stuff and the antagonistic pleiotropy. And what I mean by that is that it might be that for mammals, you know, evolution decided that it's not worth having this regeneration capability, that energy and effort is better spent on other genes. And so mammals just methylated switch this stuff off somehow. I don't know if it's methylation, we switched it off. We didn't delete it from our genome. We just switched it off. And maybe it pays now to switch it back on.
Yeah. Great.
Thank you, Korean. And we're now one minute before time, and I'm going to take Brian's question. I just want to make sure I've asked you this before in the last meeting, but I'm going to launch a poll for those who have to hop off and right at the hour, we're going to stay on for a special drawing back in. But I just want to know what your privacy preferences are for the group. And there's a lot of different varieties, we can either not record as a default, we can record only the presentation and have our afterword discussion private, and or we can record and publish as default. But I always follow up with the speakers anyways, to see if they're comfortable with it, just to make sure that that I get your answer see before those who have to go have to go. But without further ado, I'll give it to Brian, first question. Thanks. Thanks, Alison.
JOHN, thank you for the great and really important work, I would I would love to have my brain replaced with its 25 year old Barry, it's actually an improvement on my on the 25 year old version. I was wondering, it's thinking about nears question in the chat about the disruptive, complicated nature of surgery, really invasive nature of it and damaging potentially. I'm wondering whether there might be I'm sure you've thought of this and have ruled it out for some reason, but a way to, and I think you touched on this at undoing aging a couple years back. And noting the difference in the surface to volume ratio for mice and humans, which makes this a lot harder in humans. But is there some way to introduce individuals cells with and use some sort of chemotaxis to get them to go where they should go? without actually us having to silence large parts of the brain and replace that with some sort of sort of large amount of formed tissue? Or is that is that not? Is that something going to be too hard to get enough cells to get to where they need to go? And to differentiate and take on the role they need to take on structurally?
Yeah, no, that's funny, you should ask that. Yeah. So we have two projects in the lab. One is the one I presented to you today. And another one is exactly that, sort of sort of using cells that can disperse throughout the brain, and getting them to convert to another cell type, like the principle of the neocortex. So, you know, we're very interested in that, for a lot of reasons can be used for not, you know, for many, many purposes. But it won't get rid of the damage. That's there. Right. So that's why I favor this replacement of urge for rejuvenation.
Yeah. But then my so my other question that I posed in the chat would be, if I mean, I can see that a lot of functions and memory is in a way of function are distributed and can be slowly moved, not quickly. So you don't have a stroke. But you still you sign something. But it seems as though there'll be a risk that silencing large parts of the brain would actually resulted in a loss of me of memory to some degree. And that's why that's why that makes me a little bit nervous. And there are parts of me, I'd love to lose, as it's probably one of their memories we probably would like to be rid of, but, but I'd like to choose the ones that I get rid of.
Yeah, I mean, we have we have a good idea where functions lying in the neocortex now and how quickly they move. But you know, that that would need to be adjusted, you know, I don't know, according to taste or what but, you know, obviously, you don't want to silence too much at once. Right? It's going to be a balance, you know, you're like okay, well, you want and the silencing also you don't necessarily lose that it's being moved, right. So you provide new tissue before you start silencing. But still, you know, I would feel a little uneasy about silencing my whole prefrontal cortex at once. I have a lot of great tissue there waiting to take on that function. I would do it more cautious. stepwise manner. Yeah.
Right. Thank you. And hey, john, I just want to make sure that given that this is recorded, it will be published. So it will be available to others who are not in this group. Is there anything that you want people to know how they can advance your work? You already mentioned that there was potentially like a technical milestone roadmap, but what would be most useful for people to know? And to help you with your work?
Yeah. So I mean, we're, we're ready to accelerate this, we have all the key players in place that are willing to recruit experts in all these subdomains that we need for the different cell types, for the, for the bio scaffold, for the surgeries for the physiology. You know, all our collaborators are ready, we just need the funds to hire the people and get this thing going at a rate that, you know, can give us all some hope, prayer, rejuvenated brains. At the rate we're going now, we're not going to get there for us around today. So yeah, so that's where it comes down to.
Okay, well, I'm hoping that you share information, and I will put it in the show notes.
Yeah. Also the, you know, the format in which this research can be carried out. Whether it's academia, or as someone pointed out, an institute just devoted to this, that would be ideal, or, you know, hybrids between industry, academia, that's, those are all possible. We've thought about, you know, those different mechanisms, but really, to get anything started.
Yeah, very nice. I loved your suggestion with different milestones that you'd actually have. Okay, well, thank you very much. I'm hoping that you'll share with me information if people want to follow up with you. And I'll put them in the YouTube show notes. So if you see this video on YouTube, they should be in the notes. Okay. Well, is there anything else you want to tell this group otherwise I'll be closing media. Okay, well, I've already got a lot of Thank you is in the chat. And yeah, I think people were really thoroughly enjoyed this fantastic work. Very, very ambitious. And we're hoping I'll be in touch with you and then in touch with the group. And yeah, I am very, very much looking forward to getting closer this year. Thank you, Joe.