SENS5 Video: Neuron Replacement in the Neocortex

One of the more important parts of any future comprehensive toolkit of rejuvenation biotechnologies, capable of repairing the biological damage that causes aging, is the means to repair the brain in situ. The brain is in a class of its own: in theory everything other than the brain could be tissue engineered from scratch and replaced. This, in fact, will quite likely be the case for anyone who is cryopreserved and later restored to life in the flesh - easier to grow a new body than to restore the old one. But we can't replace the brain: its fine structure encodes our minds, and throwing out the old brain to replace it with even a perfect copy is just a very expensive form of suicide.

So it is encouraging to see that stem cell research is heading in the direction of ways and means to convince the brain to repair itself. This is just one thread of many needed lines of research - there is a lot more to the repair of aging than just ensuring a steady supply of new cells and refreshed stem cells that perform upkeep of tissue. But progress is progress; it all has to be done if we are to enjoy longer lives than our ancestors.

The cerebrum, as the substrate for our consciousness, memories, personality, and self-identity, presents unique challenges for regenerative medicine. Regenerative approaches must not only maintain general cerebral function, but also preserve as much as possible the details of the wiring and firing parameters that define each individual. A combination of molecular repair and gradual cellular replacement appears most likely to succeed. Toward this end, we are establishing paradigms in mice for replacing glutamatergic projection neurons in the neocortex, seat of our highest cognitive functions.

Any strategy for using transplanted cells for neocortical cell replacement is currently hampered by the inability to get cells to disperse into the existing neural tissue. To overcome this issue, we will transplant at the edge of the neocortex highly migratory embryonic GABAergic precursor cells that are engineered with lentiviruses to transdifferentiate to a glutamatergic fate once they have dispersed throughout the neocortex.

A great deal of what takes place in the laboratory these days is science fiction by the standards of the 1970s: cells transformed back and forth to order. Time moves on, and biotechnology advances.

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