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Genome Editing 101: Applications of Genome Editing

Foreword


For the first time in human history, we not only understand the language of life, but we can also manipulate it. In the past two decades, a lot of advancements have been made to contribute to the realm of genome editing. Genome editing is the combination of techniques that allow us to manipulate the DNA of bacteria, fungi, and even humans. Manipulating genetic codes have an enormous influence and can be used to increase crop yields, produce medicines in bacteria, and even cure genetic diseases.


The Genome Editing 101 series offers to explain the relevant biology of gene editing, the mechanisms by which such techniques work, and the ethical and political problems that arise from this new field of biology. It will be mainly divided into the following chapters:


1. Genome Editing 101: Central Dogma of the Cell


2. Genome Editing 101: Gene Editing Techniques


3. Genome Editing 101: Applications of Genome Editing


4. Genome Editing 101: Politics on Genome Editing


5. Genome Editing 101: Ethical Problems in Genome Editing


6. Genome Editing 101: Future of Genome Editing


Although far from being used in the clinic to cure any genetic disease, gene editing tools, most notably CRISPR/Cas9, have been shown to offer significant opportunities in many fields and contexts. The CRISPR-era is still very young, which means that it is developing at an incredibly rapid pace, and new ways of its implementation are found every year. Currently, most efforts are focused on its use in the clinic and agriculture. But, many questions and issues still remain to be answered.


Therapeutic use

The first and major field of application of gene editing techniques has been therapeutics. Many genetic diseases have been identified which are thought to be able to be cured by CRISPR/Cas9. Sickle cell disease, for example, is caused by a single mutation in the beta-globin gene. This gene causes proteins to fold in an erroneous way, which disrupts the stability of red blood cells. Consequently, red blood cells are not able to transport oxygen everywhere it is required (Demirci et al., 2019). Among many symptoms, this may cause chronic tiredness and breathing problems. It has already been shown that CRISPR/Cas9 is able to correct this mutation in cell-lines, though its clinical implementation remains yet to be performed (Demirci et al., 2019).


Besides directly correcting mutations that cause diseases, gene-editing techniques can be used to fight viral reservoirs (Nidhi et al., 2021). When HIV infects the cells that it targets, specific types of immune cells, the virus integrates its DNA into the genome of the cell. Sometimes, this part of the genome is not expressed, which makes the virus latent. At any point in time, this virus may become expressed, which leads to an active infection again (Deeks et al., 2015). Currently, no treatment focuses on this reservoir, because it is simply very difficult to remove it. Because specific sequences of the HIV genome are similar for all the evolving strains, they could theoretically be targeted by CRISPR/Cas9 to be excised and rendered inactive (Nidhi et al., 2021).


The classical example of diseases, cancer, could also be treated with a technique like CRISPR/Cas9. Tumours start to form when specific genes mutate. Two classes of genes are specifically important in oncogenesis, namely proto oncogenes and tumour suppressors (Lee & Muller, 2010). Proto oncogenes are genes that are responsible for the proliferation, or the division, of cells. When they become overexpressed, due to mutations, they are called oncogenes, the expression of which often leads to uncontrolled division of the cell. This uncontrolled division leads to the development of a clump of cells of which the integrity is no longer upheld. This is essentially a tumour. The second class of genes involved are termed tumour suppressors. These typically counteract proto oncogenes and, therefore, keep the cell stable. However, these can mutate too. When certain mutations which decrease the expression of tumour suppressors occur, the cell is much more likely to become a tumour cell as well (Lee & Muller, 2010). These two classes of genes are responsible for the overwhelming amount of cancers that can be found. Because such genes are very well characterised, they could be targeted by CRISPR/Cas9. With this technique, a mutated tumour suppressor could be corrected, and an oncogene could be rendered ineffective. Though these methods have not been applied to humans yet, they have shown incredibly promising results in mice (Nidhi et al., 2021).



Figure 1: A metaphor for oncogenes and tumor suppressors. The oncogenes result in gas, and if the tumor suppressors malfunction, there will not be any breaks to save the driver from the blast. Both are very important in a collision (Bioninja, n.d.).

Agricultural use

For thousands of years, human farmers have relied on genetic variation in plants and animals. A tomato plant that produces large tomatoes could be crossed with another that survives well in periods of less rain, for example. If this was done many times, it would be very likely that at least a few of the new crops gave rise to large tomatoes and could indeed survive dryer periods. Although it was known that these features were genetic, DNA had not been identified to be responsible for them. Ever since its discovery however, scientists have tried to artificially induce as much variation as possible in plants to create new plants that are better. This has been done in the past century by irradiation, or by treatment with certain chemicals that are mutagenic and therefore also cause mutations to arise (Mao et al., 2019; Nidhi et al., 2021).


Because the mutations induced this way are nonspecific, the process of creating new and better crops is long and laborious. However, now that CRISPR/Cas9 offers a cheap, specific and highly effective way of inducing mutations, biologists have been very excited about putting the technique to the test in plants (Mao et al., 2019). CRISPR has already been shown to work well in many different plants in a variety of contexts. Crops have been manipulated to increase nutritional properties and resistance to drought or specific pathogens, among others (Barrangou & Doudna, 2016). By rendering three genes inactive, which is also referred to as a knock-out, researchers dramatically increased the weight of rice grains (Xu et al., 2016). The fact that the global population continues to rise begs the question whether global hunger is going to be an increasing problem in the future. Scientists are hopeful, however, that gene edited crops can make a serious difference (El-Mounadi et al., 2020). Although the great potential is increasingly recognised, policy makers have been very hesitant towards allowing genetically modified crops to be commercialised. A study in April 2022 found that currently only those six crops have been approved for commercialisation (El-Mounadi et al., 2020).


Figure 2: A brief overview of the applications of CRISPR/Cas9 in te context of agriculture (Es et al., 2019).

Animal models

To study biological phenomena happening in a human body, scientists cannot simply cut open a corpse. Instead, they rely on in vivo and in vitro models, which means “living” and “in glass”, respectively. Mice, pigs and sheep are often used as in vivo models, as they are similar to humans. Not only are these models used to study normal biological processes, but they are also extensively utilised for the testing of medication, and for studying diseases (Barrangou & Doudna, 2016). Cystic fibrosis for example, is a disease for which sheep have been used in the past decades, because of the similarity in the respiratory system. Cystic fibrosis is caused by a mutation leading to only one different amino acid in the CFTR gene. This results in the malfunctioning of a protein in the membrane of cells, which in turn causes damage in the lungs, leading to constant shortness of breath and chronic lung infections, among others (Bierlaagh et al., 2021). Because a lot about this genetic disease is unknown, CRISPR/Cas9 has been used to induce the same mutation in sheep, which has turned into a very useful model of cystic fibrosis (Fan et al., 2018). Interestingly, the technique has not been used as a therapy for the disease.


Bioenergy

The call for alternative fuels is rapidly increasing, as it becomes clearer that humanity is bringing the earth, and the climate especially, out of balance. Instead of burning coal and oil, more eco-friendly options are used to not to emit any additional greenhouse gasses. CRISPR/Cas9 might even play a role in this transition as well. In 2016, researchers from the United States managed to create bacteria that were much more effective in breaking down plant material to release energy and chemicals. Normally, when such a technique is used, a lot of waste material from the plant remains, as the typical bacteria cannot transform all the plant material. The manipulated bacteria, however, managed to circumvent this issue by transforming all the material. Such a method offers great potential (Estrela & Cate, 2016).


Therapeutics, agriculture and animal models are only the tip of the iceberg of all the applications for CRISPR/Cas9. As more and more research on the power of this gene editing tool and on the side-effects becomes available, its potential is clearer every year. Perhaps in the far future genetic diseases will not be a burden to our society any more, as they can potentially all be fixed by a simple injection with a complex of CRISPR/Cas9.

Bibliography

Barrangou, R., & Doudna, J. A. (2016). Applications of CRISPR technologies in research and beyond. Nature Biotechnology, 34(9), 933–941. https://doi.org/10.1038/nbt.3659


Bierlaagh, M. C., Muilwijk, D., Beekman, J. M., & van der Ent, C. K. (2021). A new era for people with cystic fibrosis. European Journal of Pediatrics, 180(9), 2731–2739. https://doi.org/10.1007/s00431-021-04168-y


Deeks, S. G., Overbaugh, J., Phillips, A., & Buchbinder, S. (2015). HIV infection. Nature Reviews Disease Primers, 1(1), 15035. https://doi.org/10.1038/nrdp.2015.35


Demirci, S., Leonard, A., Haro-Mora, J. J., Uchida, N., & Tisdale, J. F. (2019). CRISPR/Cas9 for Sickle Cell Disease: Applications, Future Possibilities, and Challenges. In Advances in Experimental Medicine and Biology (Vol. 1144, pp. 37–52). Springer New York LLC. https://doi.org/10.1007/5584_2018_331


El-Mounadi, K., Morales-Floriano, M. L., & Garcia-Ruiz, H. (2020). Principles, Applications, and Biosafety of Plant Genome Editing Using CRISPR-Cas9. Frontiers in Plant Science, 11. https://doi.org/10.3389/fpls.2020.00056


Estrela, R., & Cate, J. H. D. (2016). Energy biotechnology in the CRISPR-Cas9 era. Current Opinion in Biotechnology, 38, 79–84. https://doi.org/10.1016/j.copbio.2016.01.005


Fan, Z., Perisse, I. V., Cotton, C. U., Regouski, M., Meng, Q., Domb, C., van Wettere, A. J., Wang, Z., Harris, A., White, K. L., & Polejaeva, I. A. (2018). A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR gene. JCI Insight, 3(19). https://doi.org/10.1172/jci.insight.123529


Lee, E. Y. H. P., & Muller, W. J. (2010). Oncogenes and tumor suppressor genes. Cold Spring Harbor Perspectives in Biology, 2(10), a003236. https://doi.org/10.1101/cshperspect.a003236


Mao, Y., Botella, J. R., Liu, Y., & Zhu, J.-K. (2019). Gene editing in plants: progress and challenges. National Science Review, 6(3), 421–437. https://doi.org/10.1093/nsr/nwz005


Nidhi, S., Anand, U., Oleksak, P., Tripathi, P., Lal, J. A., Thomas, G., Kuca, K., & Tripathi, V. (2021). Novel CRISPR–Cas Systems: An Updated Review of the Current Achievements, Applications, and Future Research Perspectives. International Journal of Molecular Sciences, 22(7), 3327. https://doi.org/10.3390/ijms22073327


Xu, R., Yang, Y., Qin, R., Li, H., Qiu, C., Li, L., Wei, P., & Yang, J. (2016). Rapid improvement of grain weight via highly efficient CRISPR/Cas9-mediated multiplex genome editing in rice. Journal of Genetics and Genomics, 43(8), 529–532. https://doi.org/10.1016/j.jgg.2016.07.003


Visual Sources

Cover image: Mafruchati, M. (2022). Identification of CF Mutations and Clinical Symptoms in CBAVD Patients. [Image]. https://news.unair.ac.id/2022/03/25/identification-of-cf-mutations-and-clinical-symptoms-in-cbavd-patients/?lang=en


Figure 1: Bioninja. (n.d.). Cancer Development. [Image]. https://ib.bioninja.com.au/standard-level/topic-1-cell-biology/16-cell-division/cancer-development.html


Figure 2: Eş, I., Gavahian, M., Marti-Quijal, F. J., Lorenzo, J. M., Mousavi Khaneghah, A., Tsatsanis, C., Kampranis, S. C., & Barba, F. J. (2019). The application of the CRISPR-Cas9 genome editing machinery in food and agricultural science: Current status, future perspectives, and associated challenges. Biotechnology Advances, 37(3), 410–421. [Image]. https://doi.org/10.1016/j.biotechadv.2019.02.006


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Sten de Schrijver

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