Why Population Sequencing Data Is Necessary to Further Clinical Gene Therapy
Abstract:
This Literature review discusses the shortcomings of current gene editing techniques and how they can be improved. Gene therapy has the potential to be the most revolutionary breakthrough in science and medicine. Its unique preventative and regenerative properties allow it to truly individualize and revolutionize treatments. This is assuming the scientists behind gene therapy can overcome their issues with genetic mutations and successfully utilize the population data approach and use the proteins necessary to obtain the targeted results.
Introduction:
In recent years science has made substantial advancements in the field of genetic editing. Genetic disorders plague modern society in many different ways and most genetic disorders are currently without a cure. Gene editing allows scientists to view genes and determine how genetic sequences translate themselves into human characteristics. From a clinical point of view, this technology could be invaluable to physicians. By being able to determine which genetic sequences translate into physical and mental ailments physicians are able to predict what illnesses each client is at risk for and enables them to take their first steps into treating genetic ailments (Dzilic et al. 2018).
Most genetic diseases are caused by the incorrect copying of nucleotides, an incorrect sequence has a domino effect on the body because if the incorrect genetic code is replicated and expressed it can have detrimental effects on the body (Bansal 2011; Liang 2015; Bansal 2010; Dzilic 2018). These malicious codes can occur naturally, be caused by environmental factors, or could be a subsequent effect of artificially editing genes (Bansal et al. 2011). While genetic editing is very promising and is the next big step in both laboratory and clinical settings the unintentional errors in the following genetic sequences can limit the success of genetic therapy (Bansal 2011; Liang 2015; Bansal 2010; Dzilic 2018).
Currently, genetic editing is done primarily with the CRISPR/Cas 9 protein. This protein is efficient at cutting and replacing specific sequences but can cause problems in the following sequences (Liang 2015; Bansa 2010). The research being discussed in this lit review discusses new methods that have been proven to more efficiently edit genetic sequences while causing fewer abnormalities along the genetic sequence. This can be achieved by using population sequencing (Bansal et al. 2010) data coupled with different editing proteins, such as NHEJ and HDR (Liang et al. 2015).
This research is important because it could transform the dream of clinical genetic editing to a reality. With more efficient genetic editing strategies (Bansal 2010; Liang 2015) and the cheapening of the procedures (Bansal et al. 2010), the widespread use of gene reading and editing will impact all aspects of medicine in terms of prevention, treatment, and regenerative growth (Dzilic et al. 2018). Research even speculates that by perfecting gene editing, specifically its regenerative possibilities, aging could be drastically prolonged by simply replacing the deteriorating, aging, cells, with the newly engineered cells (Dzilic et al. 2018).
This literature review aims to expose the problems scientists have encountered while trying to successfully, and consistently, implement gene editing as a common procedure instead of an outlandish idea. More than this, however, this literature review also explains how the faulty procedures currently used can be improved. To accomplish this the literature review first attacks the problems that each researcher has encountered, followed by the successful tactics that researchers have devolved and how to implement them. Finally, this literature review discusses what the successful implementation of genetic editing would mean for modern society, including distinct benefits in aspects of medicine affected by genetic abnormalities, specifically the cardiovascular field.
Analysis:
Downfalls of current gene editing procedures
CRISPR/Cas 9 has been the major breakthrough in science that has brought gene editing towards a soon reality. However, after CRISPR has done its task of cutting the genetic sequence, it inadvertently leads to mutations in the sequence (Liang et al. 2015). Research has found that minor genetic errors such as insertions and deletions of incorrect nucleotides are the second most prominent issue with modern genetic editing techniques (Bansal et al. 2011). These mutations, whether natural or artificial, hinder the ability of scientists to effectively predict, read, or edit genetic sequences because the proper sequence has been lost from the view of the scientists. Also, these natural errors in the genome make it hard for physicians to distinguish procedural mistakes from the ones occurring naturally, making it challenging to edit their current tactics accordingly (Bansal 2010; Liang 2015). Researchers have tested the efficiency of CRISPR in human embryos (Liang et al. 2015), the various human heart and stem cells (Dzilic et al. 2018), and additional human cells (Bansal 2011; Bansal 2010) and each cell is responsive to the sequencing power of CRISPR but each suffer from an increased amount of faulty sequences, ultimately resulting in non-functioning proteins.
Use of proteins coupled with population data as a solution
The use of poulation sequencing data seems to be the most promising solution to correcting abnormalities that occur in genetic sequences (Bansal, 2011; Bansal, 2010; Liang, 2015). Population sequencing works by collecting proper genomes from a population, in this research forty-eight individuals were used, and by inserting the proper genetic code along with the cutting and editing proteins being used scientists have seen an exponential increase in the number of abnormalities detected (Bansal 2011; Bansal 2010). Even better than simply detecting these errors is the fact that because the editing proteins have a correct base, they have a significantly higher aptitude to filter out the mutations and replace them with the proper genetic sequence (Bansal 2011; Bansal 2010). This method is so effective that researchers have achieved error rates of about two percent (Bansal et al. 2010). While this population technique is an integral part of overcoming a large hurdle for common gene therapy, it could still be improved by coupling the population technique with more effective editing proteins, such as NHEJ and HDR (Liang, 2015; Dzilic, 2018). Research has proven that the NHEJ and HDR proteins were very efficient in editing the genomes that were incorrectly cleaved by the CRISPR protein (Liang et al. 2015). Based on this research it is evident that the best way to maximize effective genetic editing is to combine all of the components, CRISPR, NHEJ, HDR, and the population data (Bansal, 2011; Bansal, 2010; Liang, 2015; Dzilic, 2018).
Future benefits of successful implementation of gene therapy
The benefits of implementing gene therapy in clinics are obvious and each article realizes that this technology would dramatically further science and medicine. Successful gene therapy has the ability to impact humans, from embryos to full-grown adults, on the most minute level of our being (Bansal, 2011; Bansal, 2010; Liang, 2015; Dzilic, 2018). These benefits would be especially potent in the cardiovascular field of medicine due to the role genetics plays in many cardiovascular-related ailments (Dzilic et al. 2018). A major benefit of proper gene therapy is its preventative characteristics; by analyzing the genetic code of individual patients physicians would be able to determine what illnesses the patient is likely to develop, enabling physicians to tailor their treatments better to each individual (Bansal, 2011; Dzilic, 2018). Also, the regenerative possibilities of gene editing could potentially stop aging in humans (Dzilic et al. 2018). A common occurrence associated with age or illness is the degeneration of cells, subsequently leading to the degeneration of tissues organs. With CRISPR and the other gene editing techniques discussed, physicians may be able to regenerate cells. Physicians can do this by programming the stem cells, naturally found in the body, to mature into any cell they need, thus replacing the original cells that were deteriorating (Dzilic et al. 2018).
Conclusion:
The research discussed all express that as of right now genetic editing is not ready to be used in a clinical setting. This is primarily due to the inability of scientists to successfully handle mutations in the genome, natural or artificial. This is the main problem discussed within these articles but these articles also acknowledge that by using population data, and better editing proteins it is possible that in the near future the amount of inhibiting mutations are dramatically decreased, and maybe then gene therapy could become commonplace in clinical settings. (Bansal, 2011; Bansal, 2010; Liang, 2015; Dzilic, 2018)
References
Bansal, V., Harismendy, O., Tewhey, R., Murray, S. S., Schork, N. J., Topol, E. J., & Frazer, K. A. (2010). Accurate detection and genotyping of SNPs utilizing population sequencing data. [accessed 2019 May 11]
Bansal V, Libiger O. 2011 Aug 1. A probabilistic method for the detection and genotyping of small indels from population-scale sequence data. NCBI. [accessed 2019 Apr 29]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137221/
Dzilic E, Lahm H, Dreßen M, Deutsch M-A, Lange R, Wu SM, Krane M, Doppler SA. 2018 Mar
14. Genome editing redefines precision medicine in the cardiovascular field. EBSCOhost. [accessed 2019 Apr 29]. https://web-a-ebscohost-com.ccny-proxy1.libr.ccny.cuny.edu/ehost/detail/detail?vid=7&sid=84195b3c-6c5a-4d2c-a967-aa922a77fe14@sessionmgr4008&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ==#AN=128486611&db=a9h
Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, et al. 2015 Apr
18. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. SpringerLink. [accessed 2019 Apr 29]. https://link.springer.com/article/10.1007/s13238-015-0153-5#Sec1
