This is such an important area of research and replacement of brain cells is the way to go. Do you think it’s important/feasible to engineer the brain cells to be refractory to inflammatory signals (NFKB signalling)? We can’t really change the microenvironment, but maybe we can change and improve the cells to be refractory to the environment?
- Absolutely, these cells are grown in culture, you can modify them any way you want. So if we have the knowledge to make them better before grafting them, we certainly can, and I assume we certainly would.
Do the grafts put out the signals that ischemic tissues put out that attract vascularity?
- In our scaffold we put factors to encourage vascularization. Their first paper shows that with stroke as the first target model, which would also be the first clinical target (not aging), it does vascularize well in the ischemic environment. There might be something in the damaged part, maybe the inflammation, that encourages it.
Is there reason to believe that – if a patient has advanced Alzheimer’s for example – will newly grafted tissue serve to remediate such system conditions, or will the newly grafted tissue quickly become similarly corrupted due to the surrounding environment? Not expecting a definitive answer, of course, just curious if there is reason for optimism in this regard.
- We don’t know, but there is a reason for optimism. We already have a lot of data for Parkinson’s. The grafts of stem cells of fetal tissue, after two decades in post mortem analysis, the cells were still there and the grafted neurons didn’t show the deterioration that the hosts didn’t show. So it isn’t 100%, we know that, but it certainly provides some time. So the same thing might be true for Alzheimer’s.
- The other thing to keep in mind is the inherent nature of plasticity of neocortex. There is always competition for function in neocortex, so whenever we need a function, that’s the function that wins out. If you put a new tissue into the brain even if it is diseased, it will be used and rerouted, so it will definitely be effective at least for some time, and then you can put some improvements into the graft as discussed before, you could address that so it is not happening in this grafts.
The pessimistic case would be that with the buildup of the damage, it will be also necessary to address the generation of the damage itself, because the damage will spread really fast once there’s a lot of it (like senescent cells, misfolded proteins), as we already see it in recent studies, therefore just adding cells won’t be enough.
- We will definitely need to look at whether the intracellular or extracellular aggregates and damage travels to new tissues, not sure whether these experiments were actually done with Alzheimer’s. Either way, in the final regeneration strategy, we will definitely need to be able to address the whole brain and replace the vascular plexus and other parts of the brain where damage accumulates as well.
This is obviously a long term project. Could you define a clear goal that a funder could latch onto for sponsoring an institute project? An inspiring and motivating milestone with a specific goal to achieve in a number of years perhaps? And how much would that cost?
- We do have a development plan with milestones. Right now for 5 years it would cost between $10-$50 million, based on the commitment.
How much have you done studies on tumors and mapping how they are destroying the tissue? How much remapping is there? Is plasticity the main thing why you think this approach would make sense? There was a lot of effort with regenerating spinal cord and they got close, but are not there yet, perhaps because the plasticity in the spinal cord is worse.
- Plasticity is essential for this approach, yes. We’re working with neurosurgeons, who do quite a bit of brain tumor surgeries and mapping with electrodes of the function when removing tumors, also by functional MRI. And they even map where the functions have moved after the surgery, even with patients with recurrent tumors where the functions were already remapped before.
What kind of tissue are you going to replace with? Is it fetal tissue?
- With the tissue we’re going to engineer including the cytoarchitecture. We could start with human fetal neocortical tissue, we do have a few experiments testing that, but it’s not a very scalable nor applicable approach. We start with embryonic stem cells and generate the cells we need from them.
How does grafting new cells affect the biological age of the rest of the brain? The approach seems to have similarities to parabiosis or bone marrow stem cell transplants in that regard? There is always the question of fixing a particular problem and regenerating a subset of the tissue only for the subset of the tissue to be swiftly aged by the environment while speeding up aging of the rest of the tissue as well?
- In the longer term we will study that, we will be looking at things like epigenetics, senescent cells, protein aggregates, and much more.
- In more end-game sense, the way this procedure could be done foreseeably is to do functional replacements when the technology is ready. So do the whole auditory complex at once, instead of neocortex first and then hypothalamus, etc. So you develop together the young parts of the brain again, to mimic how it works normally.
Are you familiar with the work of Ellen Heber-Katz, who has been for quite a few years now inducing regeneration in mammalian organ systems without grafts but merely by manipulating the metabolic environment and activating basically latent amphibian regeneration capabilities in mammals? I believe they made progress not only with the heart and bone and skin, but even with the CNS and spinal cord without grafts. Maybe you could do it with the brain as well? Any interest in that?
- That area also seems to have promise, it’s very similar in a way – you’re removing damaged tissue and getting new tissue there. But it’s not known yet whether the regenerated tissue in those mice is epigenetically young. It also might be the case that the damage made to the organs is a necessary part of the regeneration. The body doesn’t recognize some tissue as “old” and just kill it and regenerate it. You have to damage the heart or punch the hole in the ear first probably. But would be happy to follow up on this thread.
Regarding to the possible disruptive complicated and perhaps damaging nature of the surgery, I wonder whether there might be a way to to introduce individual cells and use some sort of chemotaxis to get them to go where they should go without actually having to silence large parts of the brain and replace that with some sort of large amount of formed tissue? Or is that just something that’s gonna be too hard to get enough cells to go where they need to go and to differentiate and take on the role they need to take on structurally?
- Funny that you should ask, we have two projects in the lab, one is the first I presented today and the second one is exactly that – using cells that can disperse throughout the brain and getting them to convert to another cell type like the principal neurons of the neocortex. That could be used for many purposes. But it won’t get rid of the damage that’s there, so that’s why I favor this replacement approach for rejuvenation.
If an old/dysfunctional part of the brain is silenced — even slowly — and memory is at least partly distributed, and is located in that silenced part of the brain, isn’t there a risk that memories would be partly lost, depending on the part of the brain involved? (Of course it would depend on the nature of the distribution of memory, and whether the memories would “move” enough during the silencing.)
- We have a good idea of where the functions lie in the neocortex and how quickly they move. But you definitely don’t wanna silence too much at once, it’s gonna be a balance and a process.
What can people do for your group?
- All the collaborators are ready to go with this project, we have all the key experts in place who are willing to recruit more, we just need the funds to go at it full-time and get this thing going at a faster rate. The format of funding is pretty open, be it academia, or institute (which would be ideal), or some kind of hybrid of those, or anything else, those are all possible. The roadmap we need the funds for is here.