Gene Editing and Applications in Humans

By Shun Kit Leung

Ever since gene editing techniques were first applied to human cells in 2014¹, great advances in the world of genome manipulation have been made, with more accurate, more efficient techniques having been developed. The invention of these techniques has opened the door to many new applications for gene editing in humans, including various medical treatments and even germline editing to alter human embryos.¹ This ability to directly modify the DNA sequences of a person’s cells has ever-increasing potential and practical applications, and thus remains a technology that attracts great interest from many around the world to continue its research and development. 

Genome editing is a way to add, remove or replace parts of an organism’s DNA.² All organisms require some form of DNA to contain and encode for important pieces of information about the organism, so editing the DNA sequence allows scientists to induce many different kinds of effects in the target. An easy-to-understand analogy to this would be editing an instruction manual for a build to change the final product. 

Currently, there are three main ways of gene editing in humans. These are the zinc finger nucleases system (ZFNs), the transcription activator-like effector nucleases system (TALENs), and the clustered regularly interspaced palindromic repeats system (CRISPR). Although all three are viable methods, modern day genome editing has been dominated by CRISPR due to its efficiency, accuracy as well as its ease of production.¹

Despite the different names, there are similarities between the three systems. The systems utilise engineered biological molecule complexes that can recognise and bind to specific sequences on the DNA.³The sequences that the complex binds to can be designed and changed by scientists, allowing the high degree of control and specificity these methods give. After the complexes bind with the DNA strand, they induce breaks into the target DNA via an enzyme endonuclease. These breaks trigger the cell to repair the broken DNA strands, a process which can be exploited by scientists to create random or specific changes to the DNA.³ All three systems utilise this mechanism, but what sets CRISPR apart from the other two is its ease of production. While all three systems are able to recognise specific sequences within the genome, they use different ways to do so. ZFNs and TALENs use complex, hard-to-synthesize proteins to bind to DNA, whereas CRISPR uses easy-to-produce guideRNA (gRNA) molecules. gRNA can be mass produced to high specificity, giving it a distinct advantage in terms of efficiency and cost over the other two methods. 

No matter the method used, gene editing still has many practical and incredibly useful applications in humans. For example, gene editing has been used successfully for the treatment of several diseases, including sickle cell disease (SCD) and human immunodeficiency virus (HIV). 

SCD is a disease caused by a mutation in the human haemoglobin gene HBB, changing the structure of patient’s red blood cells from its normal globular shape to a sickle shape.⁴ Not only does this decrease the stability of the cells, causing them to die early, the sickle shape also allows the red blood cells to get stuck on each other while circulating around the body, blocking blood vessels.⁵ This combination of symptoms means patients often do not have enough oxygen delivered around their bodies, creating further subsequent complications.⁵ Understanding the nature of the cause of the disease, scientists turned to gene editing for a solution. An approach that was attempted was gene addition therapy, a method whereby a normal and functional copy of the HBB gene was inserted into blood stem cells.⁴ This showed positive results in trials, but long-term effectiveness and possible side-effects are not well understood ⁴. Some other approaches that have been attempted is utilising gene editing to increase the expression levels of foetal haemoglobin.⁴ The origin of this method comes from several studies showing a correlation between elevated foetal haemoglobin levels in adults and a decrease in symptom severity caused by SCD.⁴ Scientists identified the gene that repressed foetal haemoglobin expression as a person grows up and used CRISPR to delete sections of this gene. This disrupted the gene’s ability to inhibit foetal haemoglobin expression, drastically increasing the expression levels in adults.⁴ Tests showed the percentage of foetal haemoglobin expression increased from 65% to 90%, which reduced the mutation rate of the red blood cell shape from 24% to 4%.⁶ This highly promising result is an indication that scientists are heading in the right direction, and further research is being done to refine the treatment as well as better understand any side-effects. 

Another possible use of gene editing in humans is to enhance certain traits in an individual by altering their DNA while they are still developing as an embryo. These traits can be physical attributes such as increased height or muscle mass, or it can also be genetic traits such as immunity to certain diseases. Although actual studies and experiments to attempt to enhance physical attributes have yet to be done, recent studies from Harvard researchers have identified genes associated with height development in an individual.⁷With further research done to understand how these genes can affect height, they could be gene editing targets to increase height in future generations. On the other hand, inducing HIV immunity in human embryos has already been achieved. This was done in 2018 by Chinese biophysicist He Jiankui, who used CRISPR to mutate a gene crucial for the entry of the HIV virus in a pair of twin girls.⁸ This gave them immunity to HIV, successfully creating the world’s first ever genetically modified humans. Although this example was met with great controversy due to ethical reasons of experimenting on human embryos, it shows the potential gene editing could have on the future of human physiology. 

Gene editing is a technology that has immense potential in improving human life around the world. The ability to alter the human genome gives scientists the ability to induce many specific, targeted changes, paving the road for treatments and cures for many diseases and conditions. With further research and development of relevant technologies as well as the establishment of an ethical framework, gene editing can be made safer, more reliable, and more effective, allowing its widespread application around the world. 

References:

1. Carroll D. Genome Editing: Past, Present, and Future. Yale J Biol Med. 2017;90(4): 653–659. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733845/
2. Human Genome Editing. http://www.who.int. https://www.who.int/teams/health-ethics-governance/emerging-technologies/human-genome-editing#:~:text=Genome%20editing%20is%20a%20method
3. Li, H., Yang, Y., Hong, W., Huang, M., Wu, M. & Zhao, X. (2020) Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects. Signal Transduction and Targeted Therapy. 5 (1), 1–23. doi:10.1038/s41392-019-0089-y.
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5. Hassell KL. Population Estimates of Sickle Cell Disease in the U.S. American Journal of Preventive Medicine. 2010;38(4): S512–S521. https://doi.org/10.1016/j.amepre.2009.12.022.
6. Traxler EA, Yao Y, Wang Y-D, Woodard KJ, Kurita R, Nakamura Y, et al. A genome-editing strategy to treat β–hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nature medicine. 2016;22(9): 987–990. https://doi.org/10.1038/nm.4170.
7. Guo M, Liu Z, Willen J, Shaw CP, Richard D, Jagoda E, et al. Epigenetic profiling of growth plate chondrocytes sheds insight into regulatory genetic variation influencing height. eLife. 2017;6. https://doi.org/10.7554/elife.29329.
8. Raposo VL. The First Chinese Edited Babies: A Leap of Faith in Science. JBRA Assisted Reproduction. 2019;23(3). https://doi.org/10.5935/1518-0557.20190042.