This past November, neurosurgeon Sergio Canavero connected a dead person’s head to a different corpse – a procedure he claimed to be a “successful head transplant.” His assertion was attacked by neuroscientists around the world, not least because Canavero rarely documents his exploits in peer-reviewed journals where his claims could be scrutinized. Canavero’s attempt to “heal” paralyzed patients, and potentially evade death, is radical and utopian. But what if, instead of replacing the entire brain, neurologists could replace the individual parts that make up the brain?
Neuroscientists at Albert Einstein College of Medicine recently evaluated whether replacing neurons could be a strategy to help make old brains young again. Don’t get your hopes up too high just yet – it would be difficult, but cell transplantation might be a valid approach for reversing age-related brain decline.
Our brains are different from our kidneys, livers and hips: most organs and body parts can be transplanted in (fairly) routine procedures, or even replaced with artificial counterparts. But even if we push aside the impossibility – at the moment and probably forever – of replacing our brain or its components, one problem remains: our identity is seated in the brain. This self-identity would obviously be lost in any large-scale replacement, so any strategy to “rejuvenate” the aging brain with new cells needs to preserve the neural circuits that make us who we are.
Any rejuvenation strategy needs to preserve the neural circuits that make us who we are.
Why would we even need to replace neurons in an old brain? Can’t we just “treat” aging with drugs that have anti-aging benefits? Biotech companies are trying to go down this route, but with age, our bodies accumulate a complex variety of damage. Proteins, lipids and DNA are all increasingly damaged the older we get. Molecular, cellular and organ functions are connected, so any drug that seeks to reverse aging or extend life span would need to target many different damages. So far, it is unclear whether the body’s damage repair systems could be induced or enhanced pharmacologically, and no widely prescribed therapeutics exist yet that can directly repair the damage on their own.
So, could a brain be made young again with cell transplantation? Potentially, yes. Our brains are remarkably adaptable, a feature called plasticity: the brain can re-organize its circuits and thus react to new experiences or environments. Even such complex functions as language can relocate to a different area in the neocortex when slow-growing gliomas destroy the original brain area in which language is seated.
The innate plasticity of circuits bodes well for attempts to regenerate the brain.
In aging brains, plasticity probably compensates for the effects of aging. As we age, our neurons lose complexity. Neurons change and synapses are reduced; at the same time, brain functions like memory or awareness decline. While plasticity may compensate for some of this decline, aging wins out eventually. But this innate plasticity of circuits – which are the underlying structures of our thoughts and memories – bodes well for attempts to regenerate the brain by progressively introducing new neurons. Indeed, in Parkinson’s disease patients, transplantation of fetal dopaminergic precursors in the striatum and substantia nigra formed fiber tracts that run between the brain regions years later. This is encouraging, but projections to and from the neocortex are much more complex – and the neocortex would be an obvious target for any rejuvenation attempts, as it is needed for cognition, reasoning, language, and more.
And this is where the challenges begin. Our brains are big, very big. The neocortex has about 15-20 billion neurons. To estimate a rate at which neurons could be replaced, we can take a look at the dentate gyrus of mice. In adult mice, this brain region of 3×105 neurons incorporates roughly 15,000 new neurons in six months. When we scale this up to the human neocortex, new neurons have to be incorporated at a rate of 1×109 neurons in 6 months, so all 20 billion neurons of the neocortex would be replaced within 10 years. And the new cells need to be incorporated at a rate that supports or enhances existing networks, rather than creating new ones that obfuscate self-identity. And while the neocortex is only about 2 mm thick, it covers a surface area of about 2500 cm 2. So rather than the new cells staying where they are placed, they at least need to disperse throughout the cortex.
Where should all these new cells come from? Or asked differently, which cells are best for rejuvenation? One option would be to use the neuronal precursors in an older person’s brain, and cajole them into making new cortical neurons. However, there is only limited evidence for the existence of such endogenous neural stem cells in the forebrain, and these would also undergo aging.
Using inhibitory interneurons in transplant therapy has already been explored in animal models.
Another option would be to use precursor cells from a different, younger brain. In mice, neocortical precursor cells from mouse embryos have been transplanted into the adult neocortex. In these experiments, the embryonic cells not only survive, they from cortical neurons that integrate (to some degree) into existing circuits in the adult neocortex. Even more excitingly, cortical tissue transplanted from embryos generated neurons that project to the right targets in the visual cortex and respond to light. Neurons that develop from a transplant, over time, have features similar to the “original” neighboring neurons. While these mouse studies show that embryonic cortical precursor cells could be a source for new neurons that integrate in circuits, we do not know whether these circuits function normally.
Also, using embryonic neurons is associated with ethical dilemmas. One solution for cell transplantation would be the use of neocortical organoids. These brain organoids are often generated from pluripotent stem cells, which are themselves derived from reprogrammed human somatic cells. So in theory, one of your skin cells could be reprogrammed to form a pluripotent stem cells, which is then used to make a brain organoid for transplantation into your brain. Another advantage of this approach is that brain organoids contain not only neurons, but a mixture of cell types including vascular precursors and glia cells, which support neuron growth. To some extent, these different cells may self-organize after transplantation, similar to during development.
Information doesn’t just flow through the excitatory neurons in the cortex. Inhibitory interneurons also regulate and modulate the flow of the network’s activity. An improper wiring of these interneurons is probably the underlying pathology of several brain diseases, such as epilepsy, schizophrenia, and Alzheimer’s disease.
Using inhibitory interneurons in transplant therapy has already been explored in animal models. These studies showed that interneuron transplants (in different forms) improve symptoms in the animal. Transplanted interneurons in mice make synaptic connections and induce cortical plasticity, while dopaminergic cells that were placed into a damaged brain region of rat models of Parkinson’s disease restored motor deficits.
After transplantation, interneuron progenitors can migrate long distances, differentiate into mature interneurons and modify diseased circuits. One option therefore may be to transplant interneuron precursors and induce them to convert to a cortical neuron after they have migrated from the transplant site.
Many key questions about cell transplantation, however, remain open. Transplanted cells may proliferate, differentiate or migrate unpredictably, which could in itself lead to pathologies, including tumors. The extent to which transplanted neurons are able to receive input, and are actually functional within a cortical circuit, has not been fully characterized yet. What is the optimal time point for transplanting new cells, and at what rate should transplantation occur? What is the optimal, and most ethical, source for new neurons?
If any of these strategies works, would it be sufficient to reverse brain aging? At the moment, we do not have any evidence that cell transplantation could halt aging. But looking into these options may hold some promise in preserving brain health while extending life span.
Do you think cell transplantation will one day be used to reverse brain decline in old age? Tell us in the comments!
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Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Jean M. Hébert, Jan Vijg, https://doi.org/10.1016/j.tins.2018.02.008 In Press
Interneuron Progenitor transplantation to treat CNS Dysfunction. Chohan MO, Moore H. Front Neural Circuits 2016, 10:64 Chohan MO, Moore H.