Among the coming attractions now being studied are promising genetic and epigenetic tools for editing traumatic memories, implanting transgenerational memories, modifying the effects of experience on reward behaviors to break the hold of addictions, and precision targeting of pharmaceuticals to counter brain diseases and cognitive decline.
Jeremy Day, PhD, is an assistant professor in neurobiology at UAB. His lab focuses on understanding how experience alters the brain, how those changes drive future behaviors, and developing more specific epigenetic tools to repair problems
“When only one gene is involved, a global inhibitor that acts broadly can have serious off-target effects. Our lab is interested in learning to manipulate epigenetic processes in a very specific way,” Day said. “The CRISPR system has been used to correct mutations and insert genes. We’re using a version of CRISPR that doesn’t cut DNA. Instead, we use it to create anchor points to bring epigenetic modifiers to a specific gene. This requires a few tricks to achieve specificity. We have to engineer guide RNA to target that gene.
“For example, if a gene is implicated in Alzheimer’s, we want to target that location by pulling an epigenetic-modifying protein there and have it act only there. That is the goal of our work.”
Such precisely targeted tools, which are already showing success in animal studies, together with advances in targeted epigenetic neuropharmacology, would make therapies available to treat some of the most challenging problems affecting the human brain, memory and cognitive processes.
Two areas that could greatly benefit are opposite sides of the same coin—how links to positive memories can cue reward behaviors, and how associations with traumatic experiences can trigger stress reactions.
“Fear-based memories create epigenetic changes in brain circuits. By targeting the circuits where those changes are located, we should be able to inhibit the maintenance of that memory and associations that trigger it. It has been done in animal models, but we would need new technologies to identify which neurons need to be altered so we can be sure we aren’t affecting other memories,” Day said.
“In addictions, there are very powerful memory links to previous experience and environmental cues that stimulate drug-seeking behaviors. Weakening the links to reward-motivated behaviors should make it easier to break free from addictions. However, we would want to accomplish this in a way that wouldn’t inhibit a person’s ability to enjoy everyday life.”
Genetic memory has been a topic of speculation for years, but epigenetic memory is showing some real evidence that the effects of what one generation experiences can be passed on to the next.
“Studies in mouse models that link a specific odor to a frightening experience—electrical shock—have shown that the next generation of mice will respond with fear to the same odor without the shock. The second generation also shows some increased sensitivity,” Day said. “It will be interesting to determine whether visual, tactile and sound memories have a similar affect. In humans, could this contribute to psychological difficulties, and could those inherited memories be targeted?”
Therapies that could counter brain disorder affecting cognitive abilities are another area of research that reads like science fiction.
“If we can detect Angelman syndrome early and upregulate the good copy of the gene, we should be able to prevent some of the retardation associated with the disorder. There has already been proof in principal in animal studies at The University of North Carolina,” Day said. “For patients who are already affected by diseases that cause cognitive decline, eventually epigenetic therapies may be able to enhance their function. There is already an exciting study using HDAC inhibitors to reverse neurodegeneration.”
The timeline for this brave new world is the big question. How soon will we be seeing more genetic and epigenetic therapies in real world medicine?
“We’ll see some sooner than others. Already, we’re using biomarkers to predict who is at risk, and the degree to which they are at risk. Genomic medicine is coming into practice. Five to ten years down the road, we should be seeing very specific epigenetic therapies that will make a tremendous difference in how we treat neurological disorders.”
As genetic, genomic and epigenetic advances contribute remarkable innovations to medical care, it is easy to be reminded of scientist and author Arthur C. Clark’s often-quoted Third Law—“Any sufficiently advanced technology is indistinguishable from magic.”
