Genetic modification has been all the rage in mice for some time. There are plenty of studies with mice with specific genes knocked out, genes edited to exhibit various phenotypes and genes augmented to enhance existing activity. The advent of CRISPR technology and lentiviral and adeno-associated viral vectors has created the prospect of being able to modify DNA of adult mammals including humans. The first daring self-experiments with this technology have already begun. Elizabeth Parrish, CEO of Bioviva, recently modified her DNA to increase her lifespan by increasing telomere length. She also raised her body’s levels of muscle tissue by inhibiting myostatin. These changes were at the genetic level and thus presumably permanent. Since her experiment over one year ago, she’s been doing well, and lab tests suggest that the changes have taken effect.

Given that we are now entering the age of genetic modification, the prospect for intrepid self-experimenters to explore this field is beginning and not just with the modifications pioneered by Bioviva. It would be fun to give ourselves glow in the dark hair via the addition of bioluminescent jellyfish genes to our hair follicle producing DNA. These bioluminescent jellyfish genes have already been used in several glow-in-the-dark rabbit projects and by the inventor of the ODIN DIY CRISPR kit who made glow-in-the-dark beer. However, the more sci-fi minded of us might be keen to gain inspiration from mouse studies that have augmented intelligence.

In the 1999 study “Genetic Enhancement of Learning and Memory in Mice” published in Nature, Joe Z Tsien and colleagues were able to create transgenic mice that overexpressed the NR2B gene. This gene codes for the NMDA receptor 2b which is a receptor involved in early-form long-term potentiation (E-LTP). This receptor complex is also present in humans. E-LTP is critical in generating memories that last up to 3 hours. The NMDA receptor acts as a coincidence detector that signals the cell to strengthen its electrical connections to other cells to form memories via AMPA receptor recruitment to the synaptic cleft. The mice who had this transgenic modification were able to learn spatial memory tasks at double the speed of control mice. The mice with the mutation also had normal growth, body weight, and mated normally. They had no evidence of seizures or convulsions. This lack of seizures is a significant finding because excitotoxicity via overstimulation of NMDA receptors by glutamate can often cause seizures. In the novel object recognition test, which is a test of memory for a previously seen object, the best performance in transgenic mice was seen 1 to 3 days after the test but returned to baseline after seven days.

We know that memories that last up to a lifetime encode themselves via late long-term potentiation (L-LTP) which is a process downstream of and that depends on E-LTP. While E-LTP is dependent on NMDA receptor activation and subsequent AMPA receptor recruitment, L-LTP is dependent on CREB activation and subsequent transcriptional activation of genes in the nucleus of the cell.  There have been several noteworthy findings with regards to enhancing L-LTP by creating transgenic mice with their PDE4 genes silenced. PDE4 is a well studied target for cognition enhancement. It’s such an active area of research that pre-made CRISPR kits are available to knock out PDE4B genes in mice. An experiment in 2011, “Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling“, tested the function of mice who had their PDE4D genes knocked out. This caused their levels of CREB to remain elevated after stimulation, thus prolonging and increasing CREB activation and subsequent L-LTP related gene transcription. The knockdown of PDE4D genes produced a highly significant increase in memory similar to that obtained by Rolipram, a standard PDE4 inhibitor used in rodents.

Doing a Elizabeth Parrish type experiment to increase cognitive capabilities would require a very brave self-experimenter indeed. I wouldn’t really consider doing this one myself until several had done it already or there was some well tested way to easily reverse the procedure if things didn’t go well. Still, as our understanding of CRISPR technology and genetic modification in general improves, I’m sure that we’ll eventually get to a point where these kinds of modifications and their risks will become so well understood enough that some courageous individual will volunteer to be the first person to test these or other potentially cognitive enhancing genetic modifications.