Can Genetic Modulation Attenuate PTSD?

Although 90% of the general population experience traumatic events, only a small percentage of individuals reach the threshold for post-traumatic stress disorder (PTSD) (Zannas et al., 2015). PTSD is a neuropsychiatric disorder characterized by debilitating stress and anxiety in response to a specific trauma (Banerjee et al., 2017). According to Y. Gelfand, assistant professor of Neurosurgery at Weill Cornell Medical College, a significant number of PTSD patients remain unresponsive to current drugs and therapies because their memories are deeply entrenched (Gelfand & Kaplitt, 2013). The prospect of genetic modification to alter dysfunctional brain networks is receiving heightened interest after recent discoveries in the interaction and contribution of genetic, epigenetic, and environmental factors to PTSD outcomes (Jiang et al., 2019). This discussion raises the question: To what extent is genetic modification a viable solution to alleviate PTSD?

Genetic modification encompasses two potential techniques: genetic editing and epigenetic editing. Genetic editing is a permanent technique that cuts and alters a gene sequence. Alternatively, epigenetic editing is a reversible technique that turns genes “on” and “off,” adjusting the gene expression (activity) rather than manipulating the gene sequence. Despite evidence of a genetic component of PTSD and recent breakthroughs in modification techniques, genetic and epigenetic editing are currently unrealistic approaches to alleviate PTSD due to limited medical and scientific knowledge, minimal human clinical trials, and regulatory issues.

First, it is important to acknowledge the evidence of a genetic component of PTSD, since a lack of association between genes and the disorder would immediately eliminate genetic modification as a possible solution. M. Cornelis, associate professor of Preventive Medicine at Northwestern University, claims that the evaluation of behavior characteristics supports a gene-trauma correlation (Cornelis et al., 2010). In a study evaluating the resilience of Haitian earthquake survivors, researchers emphasized the possibility of inherited resilience since Haitians and their ancestors display immense similarities in discipline and reaction after devastating and traumatic events (Rahill et al., 2016). Corroborated by researchers in Behavioral Neuroscience and Psychiatric Disorders at Emory University, the findings of the Haitian study suggest that individuals may carry heritable genes tied to certain personality traits that mediate the risk of developing PTSD (Banerjee et al., 2017)​​. Furthermore, the analysis of the serotonin transporter gene (SLC6A4), catechol-O-methyltransferase gene (COMT), and FK506-binding protein 5 gene (FKBP5) increasingly support gene involvement. The SLC6A4 gene, which regulates emotional processing, includes two variants: the S allele and the L allele (Banerjee et al., 2017). Evaluated by S. Maul, a postdoctoral researcher at the Martin Luther University of Halle-Wittenberg, meta-analyses discovered that individuals carrying the S allele typically exhibit increased stress sensitivity and demonstrate lower resilience scores (Maul et al., 2019). Because current gene analysis supports a genetic composition of PTSD, the possibility of editing techniques as a treatment for PTSD is worth exploring.

However, despite general recognition of genetic influences on PTSD, imprecise genetic loci identification and uncertainties regarding human anatomy render genetic modification unfeasible. The inconsistencies in findings between studies evaluating the role of certain genes in propelling or mitigating PTSD undermine the applicability of genetic modification to treating PTSD. A meta-analysis of five studies indicates weak correlations between the COMT gene and PTSD (Maul et al., 2019). The high variability in findings is a critical issue since strong identification of distinct molecular targets is essential for the administration of genetic and epigenetic editing techniques to PTSD patients, which is not present in current inconclusive research (Gelfand & Kaplitt, 2013).

These inconsistencies in gene association allude to greater uncertainties regarding the human brain. For example, researchers do not fully understand human functional neuroanatomy, which delays advances in identifying key genes linked to PTSD (Gelfand & Kaplitt, 2013). S. Jiang, a research assistant in the Department of Medical Genetics at the University of Alberta, delineates that multiple functional pathways are involved in regulating stress, including fear circuits and executive cognitive function (Jiang et al., 2019). Therefore, scientists need to further examine alternative biological pathways that could possibly bypass the edited gene and dilute the effectiveness of the editing technique (Zeps et al., 2021). Additionally, because of similarities in the target gene sequence, researchers cannot confidently eliminate off-target edits and damage to surrounding cells and tissues (Gelfand & Kaplitt, 2013). These gaps in medical knowledge must be addressed before further execution of genetic modification. Although recent advancements provide unprecedented opportunities to examine molecular mechanisms, the current understanding of the genomic architecture of PTSD is inadequate to support genetic modification as an effective treatment for the disorder.

Indeed, recent medical breakthroughs offer some support for the application of genetic modification to PTSD. Two genetic editing tools characterized the field in recent decades: zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) (Foulkes et al., 2019; Brandes et al., 2021). However, the stunning innovation of clustered regularly interspaced short palindromic repeats (CRISPR) revolutionized the biological sciences, propelling the field into a transformative stage (Foulkes et al., 2019). In preclinical studies, the cheaper and more efficient genetic editing tool successfully targeted multiple genes at once (multiplexing), suggesting that the execution of CRISPR is no longer an improbable hypothetical (Foulkes et al., 2019; Brandes et al., 2021).

Impressively, the repertoire of CRISPR-based tools has significantly expanded. In 2020, researchers at Peking University successfully conducted the first application of a CRISPR-based technique, aiming to delete fearful memories from rats (Sun et al., 2020). H. Sun, a researcher in the Department of Neurobiology at Peking University, emphasized that they used CRISPR-Cas9, a specific CRISPR technology that functions as a pair of molecular scissors, slicing the gene sequence where necessary (Sun et al., 2020; Foulkes et al., 2019). Co-author Yi Ming confirms that the tool could be used to treat memory-related disorders including PTSD (Papadopoulos, 2020). Shortly after, in 2021, researchers at UC San Francisco and the Whitehead Institute innovated a new style of CRISPR—CRISPRoff (Frederick, 2021). While CRISPR-Cas9 induces genetic edits, CRISPRoff produces epigenetic changes by silencing multiple genes at once, leaving the gene sequence unchanged. In a study published by the European Journal of Nuclear Medicine and Molecular Imaging, researchers evaluated long-term PTSD in veterans and found a significant correlation between PTSD symptoms and increased activity of the Tau protein in the brain (Mohamed et al., 2019). This finding is substantial as an article published by the Massachusetts Institute of Technology News asserts that researchers from UC San Francisco and the Whitehead Institute successfully used CRISPRoff to turn down the expression of Tau proteins (Frederick, 2021). While these findings highlight the potential of CRISPRoff to reduce the Tau protein activity correlated with PTSD symptoms, the results cannot be generalized since the researchers did not directly assess the efficiency of CRISPRoff for a comprehensive range of genetic components associated with the intricate disorder. Although these innovations and results are meaningful, they simultaneously accentuate a vital issue—the absence of human clinical trials.

The minimal assessment of genetic and epigenetic editing tools on humans erodes the viability of genetic modification as a suitable alternative to current treatments for PTSD. Monsen, a researcher at the Norwegian Defense Research Establishment, reports that most of the editing techniques are currently confined to basic experiments with bacteria and mice (Monsen et al., 2020). Animal models are important for understanding the psychological processes involved in PTSD, especially since living organisms exhibit similarities in underlying gene expression (Monsen et al., 2020). However, animal studies cannot explore certain vital issues that must be addressed for the implementation of editing techniques. Researchers need to acquire a greater understanding of the impact of timing, frequency, and intensity of the disorder on application efficiency, which can only be fully understood through human clinical trials due to interindividual variability (Jiang et al., 2019, Zannas et al., 2015). For instance, high intensity of PTSD may dilute the effectiveness of CRISPR interventions to reduce symptoms (Foulkes et al., 2019). Additionally, scientists need to conduct more longitudinal studies to evaluate the synergistic effect of early traumatic exposure and prolonged adult stressors on the potency of these editing techniques; unfortunately, these studies are limited due to the inaccessibility of the brain tissue in living humans (Zannas et al., 2015). Until more human clinical trials are thoroughly executed, genetic and epigenetic editing remains unfeasible.

Aside from a narrow understanding and insufficient application trials, glaring regulatory issues prohibit the administration of editing techniques to PTSD patients. N. Zeps, an adjunct professor at the Eastern Clinical School of Monash University, affirms that tighter regulations need to be implemented for greater communication of expectations between scientists and individuals enrolled in clinical trials (Zeps et al., 2021). Methodologies must be fully disclosed to highlight uncertainties and safety concerns, which are loosely addressed in some recently published studies. For instance, according to L. Papadopoulos, an editor with previous experience with the United Nations Momentum for Change, researchers at Peking University evaluating CRISPR-Cas9 on the rat brain failed to mention how they selectively determined which memories to keep and which to delete in their analysis of the administration of CRISPR-Cas9 to the rat brain (Papadopoulos, 2020). This safety issue also accentuates the question of which parties—health insurers, physicians, or participants—are liable for possible experimental errors. Therefore, academic journal publications need to include a concise analysis of the effects of off-target genetic editing and its legal implications (Brandes et al., 2021). Further regulations need to be constructed to limit distorted findings that encourage unrealistic expectations in the general public for miracle cures (Zeps et al., 2021). As epigenetic editing gains publicity, regulators and policymakers must also create standards to address issues regarding the reversibility of the editing technique (Zeps et al., 2021). Moreover, the National Human Genome Research Institute has communicated that an international framework must be drafted to define the boundary of genetic and epigenetic editing to limit the abuse of editing techniques for non-therapeutic and enhancement purposes (2017). Before these clinical and publishing guidelines are approved and released, genetic modification cannot be safely used to attenuate PTSD.

In conclusion, the combination of a restricted understanding of the underlying genetic elements of PTSD, the absence of credible human clinical research, and weak guidelines regarding current editing practices reinforce genetic modification as an unfeasible solution to alleviate the disorder at this time. Researchers must gain greater clarity regarding neurobiological processes and proceed with caution to protect the safety of participants in clinical trials. The application of CRISPR is not imminent but also not a fictional dream, as supported by recent findings regarding gene involvement and limited preclinical and clinical studies. Nevertheless, until further research is published, genetic and epigenetic editing are unsuitable to treat PTSD.

---

Cover Photo: theweek.in

Author Kelly Wu is a seventeen-year-old bioinformatics enthusiast who loves pastel colors and synchronized Pinterest boards. In her free time, she loves journaling and rearranging her Spotify playlists.

References:

• Banerjee, S. B., Morrison, F. G., & Ressler, K. J. (2017). Neuroscience Letters, 649, 139–146.

• Brandes, R. P., Dueck, A., Engelhardt, S., Kaulich, M., Kupatt, C., De Angelis, M. T., …

• Wurst, W. (2021).. Basic Research in Cardiology, 116(1).

• Cornelis, M. C., Nugent, N. R., Amstadter, A. B., & Koenen, K. C. (2010). Current Psychiatry Reports, 12(4), 313–326. doi:10.1007/s11920-010-0126-6

• Foulkes, A. L., Soda, T., Farrell, M., Giusti-Rodríguez, P., & Lázaro-Muñoz, G. (2019).

• North Carolina Law Review, 97(5), 1359–1398.

• Frederick, E. (2021). MIT News | Massachusetts Institute of Technology

• Gelfand, Y., & Kaplitt, M. G. (2013).

• Jiang, S., Postovit, L., Cattaneo, A., Binder, E. B., & Aitchison, K. J. (2019). Frontiers in Psychiatry, 10.

• Maul, S., Giegling, I., Fabbri, C., Corponi, F., Serretti, A., & Rujescu, D. (2019). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics.

• Mohamed, A. Z., Cumming, P., Götz, J., & Nasrallah, F. (2019). European Journal of Nuclear Medicine and Molecular Imaging. doi:10.1007/s00259-018-4241-7

• Monsen, I. H. L., Glenna, S., & Rjaanes, M. (2020). FFI’s Open Research Archive.

• National Human Genome Research Institute. (2017).

• Papadopoulos, L. (2020, March 28).

• Rahill, G. J., Ganapati, N. E., Joshi, M., Bristol, B., Molé, A., Jean-Pierre, A., … Journal of Health Care for the Poor and Underserved, 27(2), 580–603. doi:10.1353/hpu.2016.0100

• Sun, H., Fu, S., Cui, S., Yin, X., Sun, X., Qi, X., … Wan, Y. (2020). DScience Advances, 6(12).

• Zannas, A. S., Provençal, N., & Binder, E. B. (2015). Biological Psychiatry, 78(5), 327–335.

• Zeps, N., Lysaght, T., Chadwick, R., Erler, A., Foo, R., Giordano, S., … Sugarman, J. (2021).

• Stem Cell Reports, 16(7), 1652–1655. doi:10.1016/j.stemcr.2021.06.004