Imagine having a technological toolkit that can alter and cure the lives of over 6 million Alzheimer patients, just in the United States. Imagine these patients and their families leading a longer, healthier, and financially stress-free life. Imagine medicine reaching a point where treatment is a matter of simply turning off a gene expression. This is the future we see with the mind-boggling additions to CRISPR technology; scientists have made significant advances towards DNA editing and are continuing to modify and perfect it. Welcome to the world of CRISPRoff!
Cas-9 VS. CRISPRoff
Researchers Dr. Jennifer Doudna and Dr. Emmanuelle Charpentier’s version of CRISPR/Cas-9 allows for altering the DNA sequence using the Cas-9, however, with recent discoveries, researchers describe a new gene editing technology called CRISPRoff that has the ability to turn genes on and off — called the gene silencing effect. This design, made by researchers of Weissman Lab at the University of California, San Francisco, will drastically improve results of CRISPR’s use. While with use of Cas-9, the genetic material is permanently damaged, potentially causing more harm to the rest of the body’s DNA due to continuous replication; however, with CRISPRoff the number of risks decreases as it is completely reversible and can continue to be inherited with cell division.
CRISPRoff was designed on the basis of epigenetics — the study of the alteration of gene expression based on chemical changes in the DNA strand. As with CRISPRoff, an epigenetic modification doesn’t make any permanent changes — it doesn’t alter the genetic code itself. As gene expression varies based on chemicals, a process of methylation — the addition of chemical tags to the targeted DNA — is used in CRISPRoff. If the gene silencing effect had to be reversed back, a method called CRISPRon would be done where enzymes are used to remove the methyl groups. “Since we now can sort of silence any part of the genome that we want, it’s a great tool for exploring the function of the genome,” Jonathan Weissman says.
This new technology is still in testing. The team at Weissman has been testing it on induced pluripotent stem cells (iPSC), inducing them into neurons, and found that the silenced gene remained silenced in 90 percent of the cells. “I think our tool really allows us to begin to study the mechanism of heritability, especially epigenetic heritability, which is a huge question in the biomedical sciences,” said James Nuñez, PhD, a postdoctoral researcher in Weissman’s lab.
The Potential of CRISPRoff
Studies also show that there is some promise that CRISPRoff will help in treating Alzheimer’s. The tau protein, found in a neuron, has its main function of stabilizing the internal microtubules, used to transport substances to parts of the cell and form structures. In Alzheimer’s patients, abnormal chemicals cause the tau to detach from its microtubes, forming tangles in the neurons — disrupting communication amongst neurons.
A way to help Alzheimer’s is by reducing the amount of tau as it would help detangle the neurofibrillary (tau-caused) networks. CRISPRoff has shown positive results in reducing the amount of tau expressed in the neurons. “The question is, then, how do you deliver this to an adult? And would it really be enough to impact Alzheimer’s? Those are big open questions, especially the latter” Weissman states.
The scientific community has overcome its initial inertia on the ethical debate of the use of gene altering technologies. The topic of ethical debate has transformed from “should we use it?” to “to what extent should we use it?” The innovations are happening at such a fast pace that we seldom have an opportunity to step back and discuss the ethical conundrums they may pose. There is an ongoing conversation of using gene expression against cancer, sickle cell, or blindness. Is it too late to stop the train that has left the station? What do we use as our ethical compass to prevent going astray?
References
Dolgin, E. (2020, January 15). The kill-switch for CRISPR that could make GENE-EDITING SAFER. Nature News. https://www.nature.com/articles/d41586-020-00053-0.
Dunhill, J. (2021, April 18). New crispr breakthrough can turn genes on and off with ease. IFLScience. https://www.iflscience.com/health-and-medicine/new-crispr-breakthrough-can-turn-genes-on-and-off-with-ease/.
Eva Frederick | Whitehead Institute. (n.d.). An on-off switch for gene editing. MIT News | Massachusetts Institute of Technology. https://news.mit.edu/2021/switch-crispr-gene-editing-0414.
Ian le Guillou, T. S. A. B. contributing writer. (2021, April 12). A CRISPR on-off switch for genes CONTROLS expression without altering DNA. Scienceboard.net. https://www.scienceboard.net/index.aspx?sec=ser&sub=def&pag=dis&ItemID=2476.
Motif, A. (2021, May 26). New epigenetic editing tools can program transcriptional memory. EpiGenie. https://epigenie.com/crispron-crisproff-two-new-tools-to-earn-you-the-black-belt-in-hit-and-run-epigenetic-editing/.
Research of the WEISSMAN LAB. (n.d.). https://weissmanlab.ucsf.edu/research/research.html.
Reversible gene editing is on the horizon. Freethink. (2021, July 7). https://www.freethink.com/science/reversible-gene-editing.
Science matters series explores the next steps for crispr. American Association for the Advancement of Science. (2018, October 25). https://www.aaas.org/news/science-matters-series-explores-next-steps-crispr.
U.S. Department of Health and Human Services. (n.d.). What happens to the brain in alzheimer’s disease? National Institute on Aging. https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease.
What are the ethical concerns of genome editing? Genome.gov. (n.d.). https://www.genome.gov/about-genomics/policy-issues/Genome-Editing/ethical-concerns.
