Brain Replacement
proudly unedorsed by the FDA
"Brain replacement" refers to the proposal that the human brain could be incrementally replaced as an anti-aging rejuvenation strategy. Old brain tissue would be slowly destroyed as new tissue introduced, with redundancy and plasticity theoretically avoiding any significant loss of self or function. This approach has been popularized by longevity-maximalist scientist Jean Hebert.
This rejuvenation strategy has become increasingly popular for a number of reasons including:
increased recognition that age-associated accumulated damage is extremely difficult if not impossible to selectively repair in situ with technology on the horizon
preclinical murine studies involving neocortical transplants with evidence of functional integration
progress and optimism regarding rejuvenation strategies directed at non-brain tissues
Ostensibly multiple revolutionary breakthrough milestones are requisite for a whole-body rejuvenation strategy to work. These might be catalyzed both financially and socially via their utility in disease-specific work. With regard to brain replacement, successful replacement cell therapy could be revolutionary for the treatment of common, incurable, and severe age-associated ailments such as stroke. Such success could bootstrap brain anti-aging therapies to a much greater degree than with disease-focused longevity-adjacent small molecule development and healthspan endeavors.
However, aging-focused brain replacement at present lacks hypothetical strategies to address multiple requisite subdomains. These include specifically for the neocortex: 1) replacing within a reasonable timeframe if using straightforward multi-surgery approaches, 2) specific methods for coordinating the deactivation/removal of old tissue, and 3) addressing the possibility of regional variance in plasticity. For non-neocortical tissue (i.e. subcortical, cerebellum, and brainstem) this includes how to approach replacement given these structures play a role in encoding identity, possess an apparent comparatively lower plasticity, and are more integrated with core basic life-preserving homeostatic functions. For all brain regions there also does not yet exist a hypothetical comprehensive strategy for rejuvenating the ECM or the vasculature. Additionally, depending on age of recipient and specifics of the replacement therapies there may be age-associated brain diseases not reversed by the therapy (e.g. cancer or potentially some neurodegenerative diseases).
An overview of the contents here:
life extension context of brain replacement work
overview of putative methods for neocortical brain replacement
adding new tissue
removing old tissue
extracellular matrix (ECM) rejuvenation
vasculature rejuvenation
coordination of adding and removing tissue
white matter rejuvenation
non-neocortical brain replacement
unaddressed brain disease
re-reflecting on age-associated brain damage
translational research and stroke
next steps
Notes:
There are almost certainly errors of various types in this work. Corrections would be appreciated.
Given much of the discussed strategy lacks experimental touchstones, there is a large portion of radical speculation.
Non-brain rejuvenation context may be expanded in the future to include basic overviews when related scientists/entrepreneurs are public/ready.
Much appreciation to John S for feedback.
life extension context of brain replacement work
rationale for replacement: complex damage
The fundamental basis for promoting replacement as an anti-aging strategy for the body and brain is the accumulation of damage that is otherwise practically irreversible. As Hebert and others have noted, damage to both cellular and extracellular components includes stochastic non-enzymatic changes for which there are no endogenous repair mechanisms (i.e. that might otherwise be activated or upregulated), a myriad of damage types defying any simple constellations of small molecule and/or enzymatic therapies, and DNA mutations that with any known treatment approach preclude repair short of replacement. If replacement of tissues is possible, then whatever the mechanisms of aging are, they are sidestepped. Perhaps one day breakthroughs such as Drexler's and Freitas' nanotechnology might change this state of affairs, but that day is not today.
non-brain replacement work
There are presently exciting projects targeting the replacement of non-brain tissues that could prove complementary and synergistic with the brain replacement strategy described here. Discussion of these is presently beyond the scope of this work, and the details of those projects are not yet public.
overview of putative methods for neocortical brain replacement
While rejuvenating brain replacement is possible in theory, and in preliminary murine experiments replacement tissue appears functional, specific complete methods for performing such a therapy in humans are yet to be elucidated. That said, proposal methods include the following abstract categories for neocortical tissue:
adding new tissue
removing old tissue
ECM rejuvenation
vascular rejuvenation
coordination of adding and removing tissue
adding new tissue
Brain replacement involves, at least in part, recapitulating brain development in deploying neural precursor cells to differentiate and integrate into existing neural pathways. Replacing different brain subregions will likely involve transplantation of different mixtures of cell types matched to different phases of fetal development. Mixed cell transplants are superior with respect to survival and functional integration compared to single cell types like neural progenitor cells (NPCs). These mixed cell types could take the form of what are called organoids (pluripotent cell derived mixtures targeting reflection of specific organs or tissue types; details in section below), or specifically engineered cell-type mixtures ("bespoke neural transplants?") as employed by Hebert et al.
To avoid immunological incompatibility and to ensure a consistent source of cells, autologous induced pluripotent stem cells (iPSC) are focused on as a source for these cell grafts. Engineering subregion-dependent cells derived from iPSCs involves milestones of determining the optimal fetal tissue stage to target, as well as the specific cell-types of that stage. An overriding practical and regulatory milestone with regard to translational research is also ensuring the iPSCs are similar enough to normal pluripotent stem cells (PSCs) to mitigate legitimate concerns for overproliferation and cancer development.
why autologous iPSCs
Autologous iPSCs seem the most reasonable candidate at present for originating replacement cells. Using patient specific rather than allogenic cells reduces the probability of immune incompatibility and associated complications. Human embryonic stem cells (hESCs) do not constitute a reliable and scalable source of therapeutic cells. As described in following organoid sections, adult stem cells alone are poor candidates for replacement therapy for reasons including limited survival and differentiation potential.
iPSCs were first described in 2006 by Yamanaka who discovered how the introduction of four genes could convert somatic cells into pluripotent stem cells. He also noted that these cells bore differences compared with embryonic stem cells.
Using autologous iPSCs specifically has the additional potential advantage of genetically engineering an immunocompatible source of cells. Advantages outside the brain might eventually be growing lungs free of a cystic fibrosis mutation. Brain-specific edits might include more favorable APOE variants.
A significant hurdle to overcome in utilizing iPSCs in cellular human therapies is cancer-risk, given: 1) use of the c-myc oncogenic factor for induction, 2) possibility of viral vectors used for induction interfering with normal gene function, and 3) deployment of iPSCs-derived cells that aren't fully differentiated being possibly associated with over-proliferation.
organoids
An organoid is a 3-dimensional cluster of cells resembling a "mini-organ" and containing various cell types that emulate the organization and function of the target tissue. Organoids are derived from stem cells: embryonic, induced pluripotent, or adult. The cells are then coaxed through various pioneering tissue-specific 3d-culture methods to at least partially recapitulate development in self-organizing to resemble the target tissue, including specific protocols for different brain regions.
While there is a significant research focus now in employing organoids for disease modeling and drug screening, they also hold promise as a cellular therapy both inside and outside the brain.
CNS-specific organoids include neural progenitors as well as differentiated cells (including some ECM). The progenitor cells can migrate and differentiate based on local environment signalling molecules. Growth factors and extracellular matrix within the organoid helps guide axon extension and synaptic reconnection with non-organoid neurons (Hong 2024).
As a therapy compared to NPCs, CNS organoids have preclinical evidence of superiority with respect to increased transplanted cell survival, reduced transplant apoptosis, increased vascularization, increased neural proliferation and differentiation, and increased axonal growth (Hong 2024).
Hurdles to the translational use of organoids, in addition to the iPSC-specific issues above, include culture dependence on mouse-derived ECM substitutes associated with batch variation in subcomponents, possible harboring of pathogens, and putative immune response induction (Tang 2022).
current state of preclinical CNS organoid transplants
Significant preclinical work has been accomplished performing cerebral organoid transplantation into murine models, as well as at least one study performing transplantation into non-human primates. Following are some key findings and below that a survey of this work organized by publication date.
Key findings:
organoid grafts appear superior to isolated neural stem cells (survivability, differentiation, vascularization)
studies with hiPSCs-derived cerebral organoids assert similar outcomes to those derived from hESCs (Dong 2020)
behavioral benefits associated with grafts have been evidenced
multiple significant variables in organoid culture methods, including:
age of organoids
younger grafts (more immature cells) may be more prone to overgrowth, hypothetically leading to significant pathology e.g. brain compression (Kitahara 2020: 6 vs 10 wks)
younger grafts may be associated with increased survival and neurogenesis (Wang 2020: 55 vs. 85 days)
note: unless following the same protocols for the same brain regions, inter-study organoid ages should not be considered comparable
organoid size can significantly impact culture methods and possibly also differentiation - "small" 150-250um diameter organoids employed by Dong 2020 not requiring spinning bioreactor or matrigel
delaying transplantation from lesioning may improve integration as inferred from increased murine axon extension
organoid cells may migrate from lesion/transplant site, including to contralateral regions
only one non-human primate study, with 2 of 4 monkeys lacking graft survival
Survey notes:
Mansour et al. in Apr 2018 transplanted hESC-derived cerebral organoids into a lesion in the retrosplenial cortex of NOD-SCID mice. "Robust" integration and survival of grafts exhibited in most mice at 0.5-3 months, including "long-distance axonal projections."
Daviaud et al in Nov 2018 compared transplantation of dissociated neural progenitor cells vs cerebral organoids (both derived from hESCs) in frontoparietal cortex of 8d old P10 mice recipients after making ~1mm^3 lesion. Organoids demonstrated increased survival, differentiation, and vascularization at 2 and 4 weeks.
Wang et al. in Feb 2020 grafted hESC-derived 55d or 85d old cerebral organoids into a rat TBI model (3mm diameter & 2mm deep punch biopsy cavity in deep R motor cortex; transplanted right after injury) improved motor function with reduced gross morphological evidence of TBI. Younger organoids with higher neurogenesis and survival. Migration of transplanted cells evident at day 56 post injury, along corpus callosum to regions in ipsilateral cortex and ipsilateral and contralateral hippocampus.
Kitahara et al. in Aug 2020 compared graft development stage (6 vs 10 wks post-differentiation) in hESC-derived cerebral organoid transplantation into 1mm^3 cavities of SCID mouse cerebral cortices, as well as in primates.
One group of 7d old mice were transplanted in bilateral frontal & parietal cortices immediately post-lesioning. Another group of 6wk old mice were transplanted in R frontal cortex immediately or 1wk after lesioning. At 12wks post transplant the 6wk stage organoid grafts extended more axons along corticospinal tracts but were associated with graft overgrowth with more proliferative cells--these protruded from the lesions and spread over the cortical surface with authors expressing concern for brain compression. 10wk stage organoid grafts extended fewer axons, but this number was increased when grafting occurred 1wk after lesioning.
Four 3yo monkeys were transplanted with 10wk organoids into "2mm" cavities made in bilateral precentral gyri. 12wks later organoids survived bilaterally in only two monkeys without evidence of overgrowth, showing callosal and subcerebral projections. However, no graft survival observed in the other two!
Dong et al. in Oct 2020 transplanted 3-5 hESC and iPSC derived "small" cerebral organoids (150-250um diameter) into bilateral SCID mouse medial prefrontal cortex. Unlike preceding studies, these smaller organoids were not cultured in spinning bioreactor and matrigel was not used. Over 3 months evidence of progressive differentiation to mostly non-mitotic forebrain neurons. Projections to lateral hypothalamic regions (>4.5mm long) noted within 1 month. Functional host integration as inferred via bidirectional synaptic connections, electrophysiologic activity, and behavior (potentiated startle: increased freezing time in response to conditioned auditory stimuli). Quezada et al 2023 critique with "differentiation has thus far been abnormal after transplantation."
Revah et al. in 2022 implanted hiPSC-derived cerebral organoids into the primary somatosensory cortex of 72 newborn athymic rats (some unilateral, some bilateral). Survival and functional integration as assessed via modalities including: MRI at 2-3 months (organoids evident in 81%; organoid 9x volume expansion), functional projections to related cortical and subcortical structures, behavioral modification. Multiple complex analytic experiments performed. This study is focused more on disease modeling than therapeutics, which is emphasized by the young age of transplant recipients which limits utility for extrapolating to cellular therapies.
Jgamadze et al. in 2023 wrote up a protocol for human brain organoid transplantation into the rat visual cortex.
non-organoid mixed cell transplants
Despite the progress and success marked by the above investigations, some authors (Quezada, Hebert, et al. 2023) employ non-organoid mixed cell transplants derived from murine fetal cells, stating that with organoids "differentiation has thus far been abnormal after transplantation." Perhaps using mixed-cell constructs would have advantages over organoids. A serious caveat would be that if the transplant were to be autologous, then presumably iPSC protocols would be employed along with subsequent differentiation protocols to filter out subsets of the desired cell types. Would mixtures derived from these, rather than the murine fetal cells employed in most of these mixed-cell experiments, still offer significant advantages over organoids? While this is conceivable (could the resulting cell mixture in theory be more controlled?), this author is not aware of this work having yet been performed (let alone explicit comparative work). Additionally, there exist at least degrees of cell-type control in organoid creation.
It should be noted that laborious but informative behavioral-benefit investigations do not seem to have yet been performed with these non-organoid mixed-cell grafts, as they have been with organoids and as noted above. These are fundamental to translational applications like stroke.
Quezada et al 2023 also employed a unique layering strategy in their experiments, depositing one layer associated with a fluorescence marker for half of the lesion, then another layer associated with a different fluorescence marker. They discuss how attempting to recapitulate developmental neural layers might then better emulate normal layered neuronal circuits resulting in improved functional integration.
The question is then elicited whether iPSC-derived cell mixtures or cerebral organoids can first be produced reliably and safely enough to progress from preclinical to clinical trials. Following are relatedly a few studies associated with Hebert relating to transplantation of mixed dissociated fetal cells into mouse models.
Survey notes:
Krzyspiak et al. (with Hebert) in Mar 2022 transplanted mixed embryonic neocortical cells bilaterally into the primary somatosensory cortex of an adult mouse stroke model (distal left middle cerebral artery occlusion), finding donor-derived vessels supporting grafts (to larger extent on injured side, and towards center of grafts). Removing vascular cells (vascular endothelial cells) from grafts decreased graft size. Relevance of focusing on potential means of increasing neural progenitor cells survival for cell replacement (rather than bystander effect) benefit.
Krzypiak et al. (with Hebert) in May 2022 explored factors influencing graft size of dissociated fetal cell grafts in mouse stroke model (distal left middle cerebral artery occlusion). Graft size correlated with size of infarcts (stronger correlation in females), host age, donor cell maturity (younger E12.4 larger vs. ~E13.2 at 2wks); but not with time post-ischemia (1,3,7-days post injury tested; despite donor-derived blood vessel formation being greater at 3 & 7 vs. 1d).
Quezada et al. (with Hebert) in Feb 2023 transplanted dissociated fetal telencephalon cells in matrigel matrix into aspiration-lesioned somatosensory cortex of mice. Functional integration as assessed via survival in graft (not migrating outside) at 2 wks, vascularization/perfusion to graft (albeit less dense and more irregular vs. contralateral control cortex), neural projections (all grafts projecting to adjacent cortex, most to contralateral cortex, some to subcortical structures), electrophysiology (including V1 grafts w probes exhibiting 13wk activity consistent with contralateral control). Additionally performed layering experiments, filling half of graft lesion with one marker, latter half with another marker, and demonstrating preservation of layering at 2 wks.
quality controls
The employment of induced pluripotency and differentiation methods in the derivation of either mixed cell or organoid grafts introduces, as mentioned, the potential for various aberrations (genetic at insertion sites, expression-related based on induction media, et al.) that may be associated with abnormal cell functions or outright malignant transformation. Such abnormalities and associated risks to patients might understandably prohibit translational work. To address this suspended mixed cells might undergo quality control via flow cytometry sorting based on various criteria outside the scope of this work (for recent flow cytometry review see Robinson et al. 2023). Organoids might initially appear to be at a disadvantage in this respect given, by definition, they are a multicellular arrangement attempting to emulate in 3d the function of their target tissue. While during the cultivation of organoid cells the 3d structure may be requisite for proper differentiation and maturation, is there a reason these organoids might not be dissociated into suspended individual cells just prior to grafting? One downside might be reducing the potentially-useful ECM components getting into host tissue at the time of the graft. More importantly, is the 3d structure of organoids requisite at graft time for the apparent preclinical benefits? If these benefits can be preserved with disaggregation of the organoids, then this would allow the use of potentially-critical quality control methods.
transplants with legs
From the perspective of attempting to reduce the number of invasive surgeries, it should be highlighted again that some of the above experiments involved grafted cells that remained in the graft site (Hebert's mixed cell grafts), and others involved grafted precursor cells that migrated outside of the graft site (some of the organoid transplants). The latter may be associated with overproliferation (as was evidenced in some experiments) or perhaps more overt neoplastic transformation (when dealing with artificially inserted cells the line for neoplastic growth might be blurrier vs. cancer spectrum with endogenous cells), but also theoretically with a greater volume of tissue replacement per volume of graft (depending on many other variables including removal method and means of coordinating addition/removal of tissue).
Hypothetically graft cells might be genetically engineered to increase migration even more to further expand replacement vs. graft volume, assuming proliferation and malignancy concerns are mitigated. There has been some experimental precedent in genetically engineering cells such as microglia to then differentiate into various cell types, but there are ostensibly many challenges to implementing this in addition to integrating it with an overall coordinated cell addition and removal strategy.
removing old tissue
When new cell graft are inserted, it is assumed that a roughly equivalent volume of cells will be removed. If the newly-added cells only target the replacement of the removed tissue, then this is an approximately balanced 1:1 replacement strategy. After one set of lesions is made and brain plasticity then theoretically re-encodes the lesioned information back into redundancy with the new tissue, the patient would then be ready for another round of grafts and lesions. This straightforward strategy may however be associated with a prohibitive timeframe, depending on many variables as will be later discussed.
Rather than discrete acute lesioning of old tissue, might there be a method to better emulate pathologies like gliomas where slow cellular destruction appears to be associated with greater compensatory plasticity? Hebert briefly discusses the potential to utilize optogenetics to gradually and progressively silence old tissue to encourage re-encoding elsewhere (Hebert 2022). He specifically mentions the possibility of silencing from a pinpoint lesion outward via infecting tissue with a red light-shifted silencing channel and progressively increasing the laser light diameter of time. While still requiring surgical removal of old tissue, if possible this might increase the efficiency of brain replacement by increasing the rate at which old brain information is encoded into new tissue. Furthermore, if mobile and proliferating progenitor cells are grafted, perhaps further efficiency could be achieved via slow silencing and replication (assuming space prior to mechanical removal of old cells).
There are multiple obstacles to this optogenics approach. Firstly, how to achieve a useful transfection efficiency (i.e. how can a significant proportion of target tissue be practically transfected?)? Second, how can be the tissue be non-invasively silenced safely? Can any useful wavelengths penetrate the skull? If they can, how will inadvertent broad silencing be prevented? Alternatively could emitters fit practically within the skull and not be knocked out of place (a thin mesh micro-LED array for surface cells?)? If there is not a non-invasive means of deploying such a silencing modality, it would seem this approach lacks benefit over surgical lesioning. Thirdly, it would be important to distinguish between grafted and old tissue as multiple replacement iterations are made. Therefore, presumably it would be required both to have newly grafted tissue not be silenced with old tissue, as well as to be distinguishable intraoperatively so that only old tissue would be easily surgically removed. Perhaps transgenic markers evident on gross examination would be of utility here.
Hebert also discusses potential employment of optogenics methods in newly grafted tissue, such that these new tissues might be silenced during subsequent surgeries to verify that information has been re-encoded into the grafted tissue. Presumably then a distinct wavelength would need to be employed to not conflict with that employed for incremental silencing of old tissue. Perhaps this could pose advantageous over intraoperative neurostimulation.
It should be noted particularly in the context of discussing surgical removal of old tissue that the benefit vs. risk balance with "healthy aged" brain rejuvenations strategies is very different compared to a surgery to remove a glioma. The more intraoperatively distinguishable the new and old tissues are, and the more easily they can be functionally interrogated to verify plastic re-encoding, the more viable brain replacement strategies will be.
The removal strategy could likely benefit significantly from various expert input including e.g.: geneticists with regard to achieving reasonable transfection rates, optogenetics specialists with regard to whether non-invasive silencing is a reasonable goal at this time, and neurosurgeons grounded in basic research that might provide input on optimizing removal surgeries.
extracellular matrix rejuvenation
Age-associated changes in the extracellular matrix (ECM) may contribute significantly to age-associated brain dysfunction, and pose unique challenges for brain rejuvenation for which there are not yet coherent therapeutic strategies.
The following description of the ECM is primary derived from the paper by Soles et al in 2023. The ECM is a scaffold in which cellular tissue components are embedded. It composes ~40% off developing & ~20% of adult brains, and is composed of a mix of proteins & carbohydrates. Contributing to its scaffold organization are structured fibrous proteins such as elastin, laminins, and collagen. Filling in around this scaffold is a less-structured amorphous gel made of hyaluronan, proteoglycans, tenascins, link proteins, and glycoproteins. CNS ECM is distinguished by a predominance of non-fibrous components and 2 specialized forms of ECM: perineuronal nets (mostly surrounding a subset of inhibitory interneurons) and basement membrane (meningeal surrounding pia & vascular surrounding blood vessels). There are lifecycle-specific (i.e. developmental vs. adult) and regional differences in the composition and function of the ECM. Age-associated changes in brain ECM may contribute to age-associated decline and various age-associated neurodegenerative diseases. Therefore while the etiological details of brain aging are yet to be elucidated, a successful and comprehensive brain rejuvenation strategy likely needs to encompass rejuvenation of the ECM.
Small lesions with co-transplantation of cerebral grafts should constitute removal of a related volume of ECM with replacement with the small graft-associated ECM, hopefully but not certainly recapitulating development with respect to preserving a youthful ECM architecture. The degree of ECM replacement with these grafts would depend on the specific cell mixtures and culture conditions.
While organoids with migrating replacement cells might reduce the amount of tissue needing direct surgical replacement, it might reduce the amount of ECM being replaced (depending on details of the migratory cells).
Vasculature-associated ECM rejuvenation poses unique vessel-size-specific challenges, intertwined with rejuvenation of the vasculature as will be discussed subsequently.
Cerebral ECM rejuvenation, even compared to the nascent state of neocortical replacement, is an area that could be particularly benefited by more theoretical exploration by experts in this domain.
vascular rejuvenation
There is evidence that cerebrovascular damage accumulates with age and contributes to neural dysfunction. Related cerebrovascular pathologies include: arterial inflammation, arterial stiffening (with associated maladaptive changes such as elastic degradation), arterial weakening, decreased vascular reactivity, leaking of the blood brain barrier, loss of microvasculature, and small vessel tortuosity (Zimmerman et al 2021, Soles et al 2023). A comprehensive brain rejuvenation strategy requires addressing this accumulated age-associated cerebrovascular damage, and such damage poses significant challenges for both in-situ repair (for aforementioned reasons applying to non-vascular tissue) as well as replacement. As far as this author is aware, there are at present no existing strategies, and exploration of hypothetical avenues would be benefited by neurosurgical expertise.
Unlike neocortical tissue, the larger cerebral blood vessels cannot be sequentially replaced in small increments. Taking small chunks out of such vessels as one theoretically would for neocortical tissue replacement would result in bleeding and stroke.
One theoretical area to explore may be extracranial-intracranial bypass surgeries as a means to maintain cerebral perfusion while replacing blood vessel segments of the larger blood vessels. These surgeries are currently performed in complex cases where proximal cerebral arteries are compromised and without supplementing the distal bloodflow patients would be at high risk of strokes. However, these are technically complex surgeries and could induce the strokes they attempt to prevent via introducing emboli into the circulation or through reduced blood flow if the blood vessel connections are not performed well and strategically. This also assumes the capacity to grow and insert new blood vessels while such bypasses provide cerebral perfusion (e.g. via autologous iPSC-derived cells, rather than the cruder artificial materials employed in severe carotid atherosclerotic disease trials). If cancer/proliferation concerns are addressed further to mitigate concerns of more broadly using iPSCs clinically, new autologous vessels could be cultured, and these employed in treating common large-vessel disease, such research could be considered a fulcrum for large-vessel brain replacement. While that encompasses a lot of extreme-breakthrough "ifs," at least there is a hypothetical strategy for these vessels.
Medium-size blood vessels, on the other hand, may be too difficult to surgically sequentially replace given smaller size compared to the larger ones just discussed. They are likely also too large to be encompassed by organoid-associated neovascularization. Therefore, medium-sized vessels might constitute the most challenging segment for cerebrovascular rejuvenation.
Optimism might be most warranted with respect to the microvasculature, given the neovascularization evidenced in preclinical cerebral grafts. Perhaps sequential neocortical replacement is enough to rejuvenate the otherwise age-associated loss of microvasculature, in at least this region of the brain. Further study of how much graft-associated neovasculature recapitulates normal anatomy and function will help clarify this.
It should be noted that the above focuses primarily on the arterial side, and the venous side may include more idiosyncratic strategies based on neuroanatomy and age-associated damage accumulation.
If the grand ambitions of the body replacement camp in longevity research are ever realized, such that brain rejuvenation strategies are specifically focusing on repairing an aged brain in the context of a young body, then it is likely that age-associated cerebrovascular damage will be at least slowed in its progression. As Zimmerman et al 2021 and others note, systemic dysfunction appears to play at least a contributory role in age-associated cerebrovascular damage. The following are examples they note of age-associated changes outside the brain that are thought to contribute to cerebrovascular aging: hypertension, sympathetic nervous system activation, menopause-associated hormone changes, respiratory muscle weakening, cardiac pacemaker cell death, heart wall thickening, and impaired blood cell production. One particular notable change is how systemic arterial stiffening and associated increase in blood pressure pulsatility may directly damage downstream cerebral endothelial cells and increase BBB leakiness. Others have noted how such damage might be associated with a shift in cerebral microvasculature flow from laminar to pulsatile. Given the aforementioned noted remodeling and changes evident in cerebrovascular aging, it might be anticipated that the degree of benefit from a rejuvenated body would be related to how far the cerebrovascular damage has already progressed.
coordination of adding and removing tissue - practical sequential replacement: unswissed brain cheese
preservation of self and function
The prospect of brain replacement in general oft elicits the question of whether or not the new brain is "you," given this organ assuming the seat of our identity. If the replacement is gradual enough, the situation has been compared to Theseus's ship, where after centuries of maintenance and replacement, the ship is still considered "Theseus's ship" despite most of the original materials no longer being present. To preserve the simile, identity encoded in the brain tissue to be excised must be re-encoded in the new tissue. Literature on the plasticity of human brain tissue, in addition to the preclinical experiments above, is leveraged to both bolster this possibility and temper its theoretical breadth.
Duffau in 2014 describes a glioma (non-malignant brain tumor) case involving a region normally associated with language function, where resection of the tumor did NOT compromise language. Slow growth of the tumor allowed plastic re-encoding of language function in other parts of the brain. In even more extreme cases, children empowered by greater plasticity than adults can live with an entire cerebral hemisphere removed and, in a subset (NOT all), preserve normal lives (Kliemann et al 2019 & Moosa et al 2013).
While the brain can exhibit amazing plasticity in cases like these, it ostensibly has limits. A large stroke, or one including particularly important brain regions, is associated with increased mortality and morbidity (e.g. strokes affecting the insular cortex, or lacunar strokes in important subcortical structures like the thalamus) (Laredo et al 2018 & Gore et al 2024). Such strokes exceeding the capacity of endogenous repair and plasticity mechanisms constitute a significant source of global morbidity and associated disability.
What are the determinants of whether function and identity can be re-encoded to other parts of the brain? A very clear one is the speed of damage, e.g. a stroke with rapid destruction of brain tissue vs. slow destruction with a slow-growing tumor. The slow destruction somehow allows re-encoding that more acute conditions do not. An additional clear variable is age, with children possessing greater capacity for plastic compensation.
Another factor is location. While Duffau highlights some extraordinary outcomes, he also notes the presence of critical pathways that, if removed, would result in significant disability despite the slow tumor growth. Advocating for putting aside the traditional "localizationist" model of brain function where specific functions are mapped to specific regions, he advocates for a more "connectionist" model where function is organized into parallel, dynamic, synchronized networks. That is, the connectionist model encompasses better the functional remapping in cases like the slow growing tumor. Neurosurgeons like Duffau will uncover some of these remappings during surgery by applying electrical suppression of specific regions while the patient is awake. Despite the plasticity evident in many of these cases, he notes that cortical reorganization is particularly limited by subcortical connectivity. This may reflect some cases where neurosurgeons are forced to leave tumor behind based on intraoperative stimulation, as sacrificing the affected tissue would be too disabling.
How to reframe these variables for utility in brain replacement strategies? If brain replacement strategies involve both an acute damage component (the initial "pinpoint" lesion or chunk that can be presumed compensated for acutely) and slower gradual damage component (if could slowly expand initial damage region, assuming the genetic engineers can weave these programs alongside those of the newly transplanted/expanded tissue) then experience from acute (stroke) and chronic (slow gliomas) disease could inform the extent and tempo of replacement possible for various brain regions. The "localizationist" model is still arguably more useful in acute damage with regard to region-mapping.
Put another way, epidemiology and pathophysiology of stroke and slow-growing gliomas might inform approaches to brain replacement by: 1) highlighting the size of brain regions to be destroyed acutely or slowly while still allowing plasticity to re-encode the late tissue's information and 2) identifying regions of decreased encoding-redundancy and/or decreased regenerative plasticity that will have be dealt with via decreased size of replacement chunks or with another rejuvenation method. A comprehensive review of this is beyond the scope of this work, to the extent that significant related data exists.
surgical timespan variables for neocortical replacement
To outlay a comprehensive hypothetical strategy for neocortical replacement, a number of assumptive variables are a required, including the following.
how big a lesion can be made at a site?
how many lesions can concurrently be made?
what is the interval between surgeries?
will grafted cells be presumed to remain in the graft, or migrate out?
Too large an acute lesion, and you risk a permanent deficit by destroying tissue that encodes non-redundant information and cannot be compensated for with mechanisms of plasticity. If too many lesions are made concurrently, then there may be a negative synergistic effect where the mechanisms of plasticity are compromised (e.g. in the aforementioned "connectionist" model compensatory plasticity to an acute lesion might depend on the health/presence of disparate regions). If the initial lesions or lesion numbers are too small, then complete replacement will take too long to be useful.
Increasing the time between surgeries might allow for greater integration of the new tissue along with greater redundancy of encoded information that includes this new tissue. This could translate into better ability to accept subsequent damage and grafts without detriment. That is, if performed too early when brain networks have not adapted yet to the grafts, then permanent deficits might be evoked from loss of information not redundantly encoded. Wait too long between surgeries, and as with too few/small lesions replacing the whole neocortex would take too long to be useful.
Designing a replacement strategy to keep grafted cells within the graft zone has advantages of a lower concern for overproliferation and neoplasia. If grafted tissues could migrate outside the graft zone (e.g. through nascent precursor cells in the aforementioned murine experiments, or genetically engineered more-migratory cells) this might be useful in tandem with an expanding zone of old tissue being destroyed (if an "expanding pinpoint" of destruction could be genetically engineered). Ideally this might be said to be trying to emulate a slow-growing glioma, except without as much detriment due to the damaged tissue being slowly replaced in tandem. While this could be advantageous in reducing the overall time for complete neocortical replacement, it also might introduce greater complexity with regard to: how to coordinate lesion sites to not interfere with compensatory plasticity, a possibly reduced fraction of ECM rejuvenated, and concerns for neoplasia.
spreadsheet testing: immortality or death by a thousand cuts
Speculative estimates of total time to replace the neocortex can be conjured based on a number of variables as previously discussed. It is much easier to appreciate these estimates and variable relationships by simply inspecting the related spreadsheets.
click here for the spreadsheet at sheet.brainreplace.com
Assuming a human neocortical volume of 489 cm^3 (Pakkenberg & Gundersen 1997), as well as the probably false assumption that all neocortical lesion sites are the same with respect to redundancy-encoding, one can estimate the total time to replace the total neocortex based on the following variables (as discussed above): lesion volume, lesions per surgery, time between surgeries, and expansion out of graft region. Following are some sample calculations for total neocortical replacement based on this:
~666 years for replacement assuming:
0.5cm^3 lesion volume
4 lesions/surgery
3 years between surgeries
10% expansion
~108 years for replacement assuming:
1cm^3 lesion volume
6 lesions/surgery
2 years between surgeries
50% expansion
~73 years for replacement assuming:
5cm^3 lesion volume
4 lesions/surgery
3 years between surgeries
0% graft expansion
What are reasonable values for these inputs? Assuming a mouse lesion volume of 1.23mm^3 (from Quezada et al 2023) and a neocortex volume of 112mm^3 (Schuz & Palm 1989), the scaled size of a human lesion would be 5cm^3 (scaling factor: 4366 = 489000/112 via converting human value to mm^3). 1cm^3 is about the size of a sugar cube, so 5cm^3 seems comparatively huge and bigger than what this author would speculate could be compensated for in humans for a lesion site. It is difficult to ground the other variables in objective reference points, and there are likely some interdependencies between them (e.g. greater number of lesions per surgery might be expected to entail greater recovery time between surgeries for the mechanisms of plasticity).
What if the gradual pinpoint expansion with in-tandem new-cell replacement approach can be engineered and deployed? Using inputs of the same neocortical volume, number of initial lesions, and volume expansion per lesion per year can estimate how long neocortical replacement would take. Without any concrete guide for rational inputs, let us propose 6 initial lesions and expansion of 3cm^3 per year per lesion. This would translate to 18cm^3 total per year (~3.7% per year) and total time of ~27 years to replace the neocortex.
It should be emphasized that these numbers do not take into account other non-neocortical tissues, which likely shall require slower replacement (as discussed in subsequent sections). These numbers also do not include any removal of old brain tissue that might not be performed at the same time as tissue transplantation.
While this discussion is ostensibly very speculative, it is undertaken to highlight potentially significant aspects of this still-crystallizing hypothetical brain replacement model that could make or break specific formulations of it. If subsequent empirical data demonstrates that for the incremental surgery approach the general lesion size could not exceed 0.5cm^3 with 4 lesions/surgery, surgeries need to be spaced out at least 3 years, and graft expansion must remain at 0% (e.g. for FDA/safety-reasons), then the hundreds of years to replace the neocortex would seem to negate this whole approach. If the technology can be developed and safely deployed for a more gradual glioma-like approach, and brain plasticity is capable of preserving identity and function with ~4% neocortical replacement per year (location-specific caveats aside), then 20-something years makes this approach more reasonable.
that sure is a lot of surgery - modern surgery is not all rainbows and pancakes
The preceding preclinical transplants involving mixed cells and organoids were delivered through craniotomies: holes created in the skull. The brain replacement strategy currently sketched thus involves creating many sequential craniotomies in order to access different brain regions for replacement. Neural precursor cells have been delivered non-invasively in human trials, though as discussed this has not proved to be a cell-replacement strategy. Given the composition and size of the organoid & mixed-cell grafts, one would not expect non-invasive delivery methods to reach target brain regions.
Though many types of neurosurgeries are regularly performed, each surgery is not without risk of serious complications. "Safe" is a relative word in this context, and related to estimated benefit vs. risk to patients. It is for this reason that no ethical sane surgeon would perform the first brain replacement experiments on "healthy aged" human brains.
Additionally, while in the neurosurgical literature there exist assertions that subsequent surgeries don't necessary pose greater risks than initial surgeries, there is likely no precedent for the number of surgeries associated with the replacement of even the neocortex alone. Life expectancy and functional status might be expected to be reduced rather than increased pursuing this many-craniotomy approach to brain replacement, via developing eventually one of those low-probability but serious complications associated with these invasive procedures.
Expert neurosurgical input might strategize a hypothetical means of at least reducing the invasiveness and complication rates of a long series of multi-site brain lesioning and grafting. Some of the technological and technique advancements from tumor surgeries might be leveraged to this effect (Vadhavekar et al 2024). There are many practical related questions that would eventually have to be answered, such as "how would a proposed lesion site identified to be eloquent via neurostimulation during awake neurosurgery be handled?" Would adjacent tissue be lesioned, hoping to induce redundant encoding and an eloquency shift next time around? Or would a smaller than planned lesion be made in the eloquent region, with evidence that this would not lead to a significant deficit?
white matter rejuvenation - projection protection: phantasmagoria to Fantasia
re-establish long-distance targets
The human CNS includes long axon projections such as those in the corticospinal tract: projections of motor neurons primarily in the primary motor cortex of the frontal lobe that extend all the way down to the spinal cord. If the cell bodies of long-projecting neurons such as these in the primary motor cortex are replaced, will replacement cells be able to re-establish these long connections?
During development axonal projections have much shorter distances to go and exist in a profoundly different cellular milieu. Therefore for graft-derived axons to re-project across longer distances in a radically different environment to appropriate targets constitutes going beyond "simple" recapitulation of development. Additionally, if there might be functional benefits from new axons reprojecting to shorter-distance targets (i.e. not the original targets farther away), then even if initial graft experiments show encouraging results with function measures, such results should be interpreted with caution in the context of a brain replacement schema unless re-establishment of axons to original targets can be verified (i.e. preservation of neural circuit architecture). I.e. one might hypothesize the shorter compensatory connections to be inferior and deficits unmasked as more brain tissue is replaced.
The aforementioned studies involving organoid and mixed cell grafts variably analyzed projections from the transplant region. Following are selected comments from a few of these that suggest it is possible for both organoid and mixed cell neocortical murine grafts to project to appropriate target regions:
Mansour 2018: asserted the retrosplenial cortex organoid grafts resulted in "long-distance axonal projections to distant targets" based on markers evident in the callosum, ipsilateral cortices, and contralateral cortices.
Daviaud 2018: frontoparietal cortex organoid grafts with evidence of "long projections" but without an "organized projection pattern" (i.e. apparent failure to reconstitute normal regional brain circuity), the authors speculating could be due to study duration
Dong 2020: medial prefrontal cortex organoid grafts functionally projecting >4.5mm to regions including lateral hypothalamus
Revah 2022: primary somatosensory cortex organoid grafts in newborn rats projected to ipsilateral auditory, motor, somatosensory cortices; as well as to subcortical regions (striatum, hippocampus, thalamus).
Krzyspiak 2022: primary somatosensory cortex mixed cell neocortical grafts projected appropriately to motor cortex, striatum, and surrounding somatosensory cortex.
Quezada 2023 found somatosensory cortex mixed cell neocortical grafts projected all to adjacent cortex, most to contralateral cortex, and some to subcortical structure.
Most interestingly Kitahara 2020 mouse frontoparietal organoid grafts exhibited corticospinal tract projections from motor cortical regions all the way down to the contralateral spinal cord! In the 2 of 4 monkey transplants where grafts survived projections were traced to neighboring cortical areas and subcortical regions, extending towards the corpus callosum and striatum, but not extending further. The authors comment that the latter incomplete extension may be due to the short study duration.
The above studies suggest that, despite the incredibly longer distances and radically different cellular milieu compared to embryologic development, it appears that the signals and mechanisms for targeting at least some axon pathways is preserved. Further studies involving complex circuity, long pathways (like the corticospinal tract), and longer study duration might bolster this grounded optimism. To the extent that there might be incomplete projections with longer study duration, there might hypothetically be methods to engineer solutions such as artificial projection guides in the projecting neurons or along the target region.
axonal skeletons in your closet vs. slightly-used second-hand axons
Assuming initial incremental replacement grafts can re-establish long-distance connections, there remains the issue of cellular debris from pre-existing now-disconnected axons: CNS myelin sheaths are not readily cleared away from injury sites, with "ghosts" of prior axon paths remaining for years or indefinitely. This may be of functional consequence as this debris may act as a barrier to axon regeneration (Varadarajan et al 2022). The significance of these axonal remains would only be expected to compound as more brain tissue is incrementally replaced.
Perhaps there is a means of emulating the peripheral nervous system in more efficiently and effectively cleaning up degenerated axons. Alternatively perhaps there is a means of connecting newly grafted tissue to the existing axon structure that would otherwise presumably undergo Wallerian degeneration (though this may introduce an issue with needing to rejuvenate these axons if e.g. accumulated myelin abnormalities or damage). There may be overlap in this area of research with spinal cord repair work. At present it seems there are only these speculative hypothetical solutions to the axonal skeleton problem.
rejuvenating white matter tracts: white matter tracts matter
White matter tracts represent a particular challenge to the brain replacement paradigm, beyond addressing just the consequences of degenerated axonal remnants. They ostensibly represent part of the significant encoding of identity, including main conduits between neocortical regions as well as between neocortices and other brain loci.
White matter undergoes multiple changes in "healthy aging" (Liu et al 2018). These include a reduction in volume, tract disruption, and loss of myelination. These changes are associated with functional deficits including impairments in sensorimotor and cognitive function, as well as psychiatric disorders. White matter tract dysfunction may also be implicated in other age-associated neurodegenerative diseases.
Even if grafted neocortical tissue can re-establish axonal connections and axonal remnants can be dealt with, white matter regions consist of more than just axons: glia, ECM, and vascular components in these regions will also likely require rejuvenation. While small chunks might be taken out of neocortical gray matter without serious functional consequences, it is more difficult to envision such functional resilience to similar insults to white matter regions where many axons are concentrated. CNS axons are notoriously less regenerative compared to the peripheral nervous system. Injury to even a small region of white matter can irrevocably disrupt many long projections, leading to degeneration of these axons and often cell death of the associated neurons which may be located far away.
Is there a way to target replacement of the non-axonal components of white matter without disrupting the axonal connections? While one might envision migratory progenitor cells to perhaps repopulate glial elements, addressing the removal of old glia and rejuvenating the ECM and vasculature seems a more difficult problem. This is another area that might particularly benefit the brain replacement paradigm with expert brainstorming.
non-neocortical brain replacement: how far down do we go? brain limbo and new ideas for older tissue
The current discussion centers around the neocortex given it encodes much of what we are, as well as it being more readily amenable to initial experimentation. But "we" are encoded further in structures below the neocortex. The rest of the brain (subcortical structures, cerebellum, brainstem) likely contribute significantly to who we are (Tzounopoulos & Kraus 2009 & Skoe et al 2013).
Thus if one day body transplants and spinal cord repair become a reality, rejuvenation of non-neocortical brain structures will have to be addressed. Attributes that will likely make at least some of these structures more difficult to rejuvenate through replacement compared to the neocortex include: 1) reduced plasticity, 2) more difficult safe surgical access, and 3) performance of critical life-preserving homeostatic functions.
As discussed in the above plasticity section, it is noted that subcortical structures can exhibit decreased plasticity compared to the neocortex, and this likely translates into smaller foci of damage that they can tolerate without significant functional detriment.
With respect to surgical access, it is difficult to find complication rates for neurosurgeries by target brain regions. However, they would be confounded by the comorbidities necessitating the neurosurgeries (e.g. brainstem tumors increase perioperative risk beyond the risk of operating on a "healthy" brain). That being said, a non-neurosurgeon might assume that deeper (have to go through or push aside tissue that may be damaged) and brainstem structures might pose increased surgical difficulty and be associated with higher complication rates compared to superficial neocortex. Alternate surgical approaches (e.g. intraventricular) might represent some mitigation to this generality. Expert neurosurgical input could be of utility in clarifying the hypothetical landscape of brain region replacement (absent common neurosurgical indications such as tumor or epileptic focus) by estimated difficulty and probability of complications.
While limitations of compensatory plasticity may for some brain regions necessitate a slower replacement rate or alternative rejuvenation mechanisms, other regions may not be amenable to the neocortical replacement rate due to constituting parts of critical homeostatic circuity (e.g. control of respiration, blood pressure, heart rate). There may be some hope for replacement if other structures can temporarily overtake these homeostatic controls, such as the high spinal core possibly acting as a backup respiratory drive center (Ikeda et al 2016).
unaddressed brain disease
Even if the above brain rejuvenation strategies are fleshed out and successful, the brain would not be immortalized. While an in-tandem rejuvenated body would be expected to have a positive impact on brain health (e.g. the restored elasticity of the aorta contributing to normalizing cerebral perfusion), there remain assailants of brain integrity including:
cancers: primary CNS tumors or metastatic disease
neurodegenerative diseases: e.g. Alzheimer's
While behavioral changes might mitigate a bus-impact undermining one's immortality strategy, cancer and neurodegenerative diseases require complementary life-extension strategies.
Translational work in stroke may be informative with regard to how brain replacement may impact these diseases. Stroke patients with cerebral transplants might exhibit increased or decreased incidence of neurodegenerative diseases (new cells lacking deleterious aggregates, beneficial paracrine effects?) and neoplastic conditions (e.g. iPS mutations increasing, transplanted immune cells decreasing?), which could inform improved brain rejuvenation strategies.
re-reflecting on age-associated brain damage
The discussed major hurdles for brain replacement and current lack of hypothetical approaches for some aspects of this compel revisiting in-situ repair in an overall life-extension strategy.
The argument remains valid that there exists a plethora of age-associated damage types that defy even theoretical approaches for reversal. Replacement remains an intriguing defensible hypothetical method for addressing much of the neocortex, particularly if genetic engineering might assist in coordinating a more gradual addition and removal of cells outside acute surgeries to compress the surgical timescales. Neocortical replacement still would seem to wonderfully sidestep the many-formed complex age-associated damage. However, rejuvenating non-neocortical regions as well as the ECM and some vascular components of even the neocortex appears to pose much more of a challenge for simple replacement as discussed above. How might maximalist scientists navigate this apparently dour situation?
Despite the many forms of age-associated brain damage, this does not mean that all such damage is equal with respect to deleterious effects on brain homeostasis and function. Though a singular type of damage fails to characterize brain aging, this does not mean there does not exist a spectrum of damage from less to more deleterious (at least at some timepoints, and accepting potential interactions and non-linear/non-exponential impacts). In the absence of hypothetical strategies to replace some types of brain tissue, at least consideration of a hybrid replacement approach including in situ repair is warranted. Ostensibly the latter cannot address all damage for reasons discussed, and is more complex than the neocortical replacement approach, but what alternatives are there? In our current state of ignorance, might a hybrid replacement-repair approach be considered now the best reach for brain rejuvenation "escape velocity?"
As the flashlight of science is aimed at these many unknown unknowns in triad hues of hypothetical replacement and in-situ repair strategies, preclinical studies, and diseased-focused translational work; perhaps a more grounded and robust brain rejuvenation strategy can be illuminated. The most defensible approach thus appears to be promoting brain replacement for amenable domains discussed, in-situ hybrid approaches where hypothetical strategies exist for the rest, and a blank chalkboard to brainstorm for regions lacking in either approach.
translational research and stroke
Given the discussion on how acute neocortical damage is associated with decreased or no capacity to compensate, stroke may at first seem unamenable to target as a translational clinical milestone. However, there are two factors that dissolve this apparent contradiction: 1) deployment of neural grafts in stroke strives for a different goal than that associated with aging rejuvenation, and 2) there is a radically different benefit to risk profile in stroke vs. a proactive aging therapy.
With regard to the first factor, that brain replacement for stroke and aging target different goals, one might abstractly consider the brain as encoding two different types of information. On the one hand there exist genetically-encoded programs and circuit pathways for basic and specialized functions that have been tuned by countless iterations and selection-factors of evolution. This might include the core networks for basic motor function, visual processing, and generalized networks for face identification. On the other hand there is experiential information learned from the environment: e.g. the color and shape of maple tree leaves next to a childhood home, voices of ones' parents, or how the stars looked in the sky when drinking the blood of your enemies. Obviously there should not be considered a hard dividing line between these two categorical poles, given wealth of knowledge on how experience tunes the first type of basic circuits. That being said, logically genetics can ostensibly encode at least the prime characteristics of some types of encoded information (the former type), and cannot encode information that can only come from the specifics of life experience.
Whenever evaluating a therapy that may irreparably damage brain tissue, consideration is implicitly given to the preservation of both these types of encoded information. With stroke, whatever is lost after the limits of the compensatory recovery functions have been reached, is lost. Barring some means by which experiential knowledge apparently deleted in stroke is actually dormantly encoded in redundant circuits, no amount of scientific acumen will bring this back. This tautology is stated for emphasis. From this bleak starting point, however, scientists can aspire to utilize cellular therapies to perhaps recover the genetically-encoded programs via emulating development. This translational hope is grounded in the fact that these circuits have been formed previously in development. Restoration of even some of these circuits could in theory e.g. restore movement or sensation in half of the body. Even if a chunk of experiential information is still consigned to oblivion, that restoration of some basic function could for stroke patients translate into immense improvement in the quality of life.
Thus for brain replacement in the context of an anti-aging rejuvenation strategy we are loathe to consider emulating stroke given the potential permanent loss of encoded information, that does not mean that replacement therapies offer no benefit when stroke is the starting point. That is, different goals are therefore sought: in aging we seek to continuously preserve genetically-encoded programs as well as experiential knowledge, while in stroke we start with deficits likely in both and seek to restore only the genetically-encoded programs.
This brings us to our second point: there exist radically different benefit vs. risk profiles for brain replacement in aging vs. stroke. Some strokes produce deficits that wreak destruction on quality of life to the point of inducing suicide. The risks that such patients are willing to take, as well as the risks that their clinicians are ethically willing to take, are going to much different than the risks that patients and clinicians are reasonably willing to endure to proactively attempt staving off aging in otherwise healthy individuals. The goal of living forever is more than a little undermined if while pursuing proactive anti-aging therapies one dies otherwise-healthy on the operating table.
next steps
Stroke-focused translational work appears now the fastest path to developing a longevity-oriented brain replacement strategy. Thus overcoming the massive hurdles discussed above for a first successful stroke trial using an autologous cell-replacement therapy should be the most important next milestone for brain maximalists.
Why is this translational work so important even as there is so much left to explore in murine models, such as cultivation and transplantation of non-neocortical region tissue types? While preclinical work is ostensibly necessary to get to trials, there may be elements of the lesion murine experiments that are difficult or impossible to extrapolate to humans with strokes. For example, the only primate study had a graft survival rate of only 50%. Variables like cell mixture composition and target region selection may require significant alterations beyond simple relative scaling-up of rodent lesion studies. Additionally, humans introduce a more complex behavioral/intellectual outcome domain such that early translational work may provide significant guidance on how large regional lesions can be while still allowing complete recovery with grafts (expanding glioma case studies can provide only so much guidance), or this work may suggest modifications in the cell therapy to increase post-stroke benefit (and potentially in tandem the recoverable lesion size in an incremental replacement strategy). In summary, early translational work in stroke may profoundly inform the iterative basic science progress towards effective brain rejuvenation. Exploration of what dimensions of translational stroke research could be most fruitful may be the subject of a future article here.