VitaDAO is sending a recommendation to fund Jean Hebert’s work on Brain Cell Replacement Therapy. Jean Hebert is a leading expert on the subject of brain aging and he is creating methods for brain cell replacement for use in stroke with his laboratory at the Albert Einstein College of Medicine.
A big challenge facing tissue and organ replacement as a strategy to beat aging relates to the brain. The brain, especially the neocortex - the part that underlies our highest cognitive functions and self-identity - cannot obviously be replaced as a whole organ.
The neocortex can be replaced by progressively replacing tissue areas over time without significant disruption in function or self-identity (reviewed by Hébert and Vijg, 2018; and see for example Duffau, 2014, who documents the relocation over time of language without a disruption in speech in older adults in which the original language center was slowly destroyed due to disease). In addition, immature neocortical cells transplanted in mature neocortices develop normal synaptic connections and can respond normally to sensory input or elicit motor output (Falkner et al., 2016; Michelsen et al., 2015; Espuny-Camacho et al., 2013; and our data at doi.org/10.1101/2021.02.27.433204). These studies support the feasibility of age reversal for the neocortex via progressive tissue replacement.
Mechanism of Funding
This deal has been subject to several months of due diligence from the VitaDAO longevity working group, and the group has consulted with industry experts, such as the Foresight Institute and Apollo Health Ventures, to assess the feasibility of this project. While the project is highly ambitious, Jean and his team represent some of the most capable experts in the field.
VitaDAO is evaluating several options for funding Jean’s project. Apollo Health Ventures is currently creating a very early stage company around Jean and his work. We are proposing funding either 1) a small piece of Jean’s work via an IP-NFT and a sponsored research agreement, 2) investing directly into the company that is being created around Jean’s work via Apollo Health Ventures or 3) some combination of both. This proposal recommends VitaDAO acts on option 3) investment into the company being created by Apollo Health Ventures and additional funding via an IP-NFT.
For more information about Jean’s Brain Cell Replacement Therapy project, please view this video summary from Jean’s presentation at the Foresight Institute.
Aging at its core is the accumulation of macromolecular damage. For example, damage to the extracellular matrix or to DNA cause the other hallmarks of aging (reviewed by Fedintsev and Moskalev, 2020; Schumacher et al., 2021). Elastin, an essential component of blood vessel walls, provides an illustrative example. Elastin progressively accumulates damage over our lifetime leading to dysfunctional blood vessels and loss of tissue function throughout the body. The damage to elastin is complex (glycation, carbamylation, breakage, racemization, and others). However, elastin is only one of many proteins that accumulate damage. And complex damage occurs not just to proteins, but also to lipids, carbohydrates, and DNA. If we do not address this damage, we will fail to significantly extend the human lifespan. These stochastic forms of damage are unlikely reversible pharmacologically, enzymatically, or genetically without disrupting the delicate balance of life-sustaining biochemistry (i.e. without overwhelming side effects). This is a major blind spot in the longevity field. On the other hand, tissue replacement would eliminate all forms of damage at once, and may therefore be worth exploring. Every part of the body (except the brain) has been surgically replaced in humans using donor tissues and organs, demonstrating implementability. In a growing number of cases, lab-grown cells and organs or increasingly sophisticated prosthetics are used as replacement parts. Regenerative medicine is thus on track to being able to replace all cells and tissues of the body. A big challenge facing replacement as a strategy to beat aging relates to the brain. The brain, especially the neocortex - the part that underlies our highest cognitive functions and self-identity - cannot obviously be replaced as a whole organ. Yet, the neocortex can be replaced by progressively replacing tissue areas over time without significant disruption in function or self-identity (reviewed by Hébert and Vijg, 2018; and see for example Duffau, 2014, who documents the relocation over time of language without a disruption in speech in older adults in which the original language center was slowly destroyed due to disease). In addition, immature neocortical cells transplanted in mature neocortices develop normal synaptic connections and can respond normally to sensory input or elicit motor output (Falkner et al., 2016; Michelsen et al., 2015; Espuny-Camacho et al., 2013; and our data at doi.org/10.1101/2021.02.27.433204). These studies support the feasibility of age reversal for the neocortex via progressive tissue replacement.
Tissue replacement (cells, tissues, organs, etc.) is not a new idea - it’s one of the possible approaches to defeat aging. If replacements are ever going to be useful, we need to figure out how to apply them to the brain. Replacements per se, in terms of implementation, are not that problematic. Every part of the body was surgically replaced over the last few decades to treat disease and injury. The problem is with the replacements themselves, so there is a need for lab grown organs and improved prosthetics. Progress is painfully slow, and investments are rather limited. Eventually, we will be able to replace all parts of the body, except the brain.
The brain is the most important part - you don’t want to live in a young body with a senile brain. It cannot be replaced as a whole organ, however, but could be replaceable progressively via brain cell replacements without losing our identity. The human brain is mainly neocortex. That’s where our thought patterns and self-identity are stored. The neocortex is extremely plastic by nature, functions can change their substrate over time. In cases where older patients (50 or 60 years old) had benign tumors removed from their brain, and the tumor was where the language centre was, we have observed that the transfer of function must’ve happened progressively, because they didn’t lose the ability to speak. Therefore, it should be possible to do this progressively with an intervention that provides young naive tissue over time, as well.
The other reason why tissue replacements make sense is the evidence from studies that were putting in immature precursor cells for the neocortex and showing that these immature precursors differentiate into neurons that make the appropriate connections to distant parts of the brain in model animals.
Hypothesis on General Process for Brain Cell Replacement:
- Aging brain loses a lot of volume, which creates space.
- We implant new grafted functional tissue in that space.
- We could silence the old tissue and the area of neocortex we want to get rid of, that is nearby the new grafted one. That should be possible pharmacologically.
- Then we could remove that old tissue once it’s silenced and not used anymore and the functions have moved to new locations, in particular, this naive implanted substrate.
- This progressively regenerates the neocortex in that area.
We are trying the general process described above in mice – basically doing a lesion and using it as a platform for rebuilding functional human neocortical tissue. When vascular cells are included in the grafts, which is important to maintain the health and function of these grafts, we find that the vascular cells form blood vessels. There’s still a lot that needs to be done before this grafted tissue is functional. There are still many cell types missing. Replacing neurons and blood vessels is not enough; the neocortex is comprised of many cell types. We are now working on including many other cell types, which we fortunately know how to generate from human embryonic stem cells. The first aim is to assemble all the cell types we need to have a complete cortex and to have them organised. There’s a certain cytoarchitecture for a proper connectivity of the neurons in the cortex. Different layers have different densities with different identities or cell types. So we’re developing a scaffold that supports survival, differentiation, and integration of both neurons and vascular cells, whether human or mouse.
In parallel, we want to show a proof of principle for neocortical tissue replacement with an experiment. We train an animal to do a particular task that requires multiple parts of the neocortex. The task needs to go through one small part of the neocortex, the motor cortex. Next, we introduce a lesion in that part and put a graft in and see whether the removal of the motor cortex created the expected functional deficit. With the help of electrodes inside the graft, we can see whether the graft differentiates enough, so with behavioral retraining, the deficit is fixed by re-routing the function through that implanted and now activated graft. Once that happens, we can silence the graft using a transient channel with a drug, and show that the animals cannot do the task again. We can then see it activate again and see them do the task again, once the drug clears out. This will be the first demonstration that neocortical tissue replacement is possible. This has not been shown yet, so it’s an important landmark experiment.
Progressive neocortical tissue replacement will require the reassembly in situ of multiple precursor cell types in the correct ratios, relative differentiation stages, and cytoarchitecture to allow the new immature tissue to differentiate normally. To date, we have grafted human neuronal precursors with human vessel-forming vascular precursors, resulting in efficient neuronal and vascular integration with the host (the adult mouse neocortex is used as a test platform for building human tissue). An essential next step is to add astrocytic precursors to the grafts. Astrocytes are essential for proper maturation and function of neurons and for the blood-brain-barrier (BBB). Outcome measures of neuronal function and BBB integrity will include comparing grafts with and without astrocytes.
We are proposing funding either 1) a small piece of Jean’s work via an IP-NFT and a sponsored research agreement, 2) investing directly into the company that is being created around Jean’s work via Apollo Health Ventures or 3) some combination of both.
Methods of engineering in situ neocortical tissue, even partial, have not been described or patented, providing ample opportunity for IP. Even partial engineered neocortical tissue could be used not only for brain repair and age reversal in human patients, but also for brain disease modeling and drug discovery using the human brain tissue (with human neurons, vasculature, astrocytes, and BBB) in mice.
- Agree (with revisions)