“Too many of our preferences reflect nasty behaviors and states of mind that were genetically adaptive in the ancestral environment. Instead, wouldn't it be better if we rewrote our own corrupt code?”
Being almost at the end of this series on Supernatural: No More Sci-Fi, Human Enhancement Is Now Real, quoting David Pearce gave an insightful starting point for today’s article on gene editing methods.
To introduce you to the topic, a brief history of how gene editing CRISPR was discovered will open this article letting you feel onboard with a tight seatbelt. Moreover, we will continue our journey navigating across clinical studies in which CRISPR was already applied and followed by a short preview of what will be discussed in our last article concluding this enhanced series on Supernatural.
What is CRISPR?
Acronym for Clustered regularly interspaced short palindromic repeats (CRISPR), or more precisely CRISPR/Cas9, is a technology to accurately edit the DNA of any genome. CRISPR is a series of short repetitions in bacterial DNA representing a prokaryotic adaptive immune response against external viruses by storing bacteriophages’ genetic information. Hence, in the form of RNA molecules, CRISPR sequences act as messenger converting genes into proteins; indeed, based on the previously stored genetic content this system would generate an appropriate immune response when approaching another viral infection to protect prokaryotes.
From Watson and Crick’s initial DNA discovery to the first genetically modified animal in 1974 (1) to early genetically modified foods in 1994 and to the Human Genome Project in 2003, gene editing has been always a challenging task and more still has to come (feeling just right at the knee of that exponential curve, that our ExO community well know!). From the initial discovery of CRISPR/Cas 9 and its further development into a genome engineering technology, this finding represents the contributions of several scientists and research teams across the globe that can be incorporated into a historical CRISPR timeline.
Accidentally discovered in E. coli by Yoshizumi Ishino and his team in 1987 (2), a few years later in 1993 CRISPR was found in Mycobacterium tuberculosis by J.D. van Embden (3). Successively, the understanding of CRISPR’s role as an adaptive immune response was identified in early 2000 by Mojica and co-workers, who notice that spacer sequences were similar to those typically found in bacteriophages, viruses, and plasmids (4) (5). Later on, in 2012 George Church, Jennifer Doudna, Emmanuelle Charpentier, and Feng Zhang hijacked CRISPR/Cas9 as an innovative method for genome editing while paving the way to research and studies in this field, in which Science named CRISPR Breakthrough of the year in 2015.
More insights on CRISPR/Cas9 can be found in the video below:
What CRISPR is used for?
Giving the opportunity to directly target and modify the genomic sequence in almost all eukaryotic cells, the evolution of genome editing highlighted the possibility to create more precise animal and cellular models of pathological processes supporting advances in biotechnology and biomedical research. Nevertheless, the great progress of gene editing and its potential in developing innovative therapies for clinical applications still remains under investigation although very promising technology in understanding deeper biological mechanisms underlying diseases (6). Recently, a few approved CRISPR gene therapy trials have been designed for patients affected by severe diseases or cancers although the application of this technology remains a debated topic, especially when involving its application for less debilitating diseases or non-clinical objectives (7).
CRISPR gene editing emerged in genetic engineering as an ultimate tool allowing changes in the organism’s DNA. Already adopted by scientists in several research projects, CRISPR/Cas9 quickly emerged as a promising treatment in multiple life-threatening diseases.
A study published in Scientific Reports from the Columbia University Medical Center (CUMC) and the University of Iowa implemented CRISPR to repair a genetic mutation implicated in retinitis pigmentosa (RP), which is an inherited condition causing degradation of the retina leading to blindness. This remarkable research was a step toward the possibility of replacing a defective gene related to a sensory disease in stem cells, derived from a patient’s tissue.
However, a new reversible CRISPR method was developed to control gene expressions without changing the underlying DNA sequence. This method was defined as an “on-off switch for gene editing.” Thus, genes can be activated or silenced based on chemical changes to the DNA strand; what in science is called “epigenetic.” Considering clinical and research studies in which this alternative method would be applied, CRISPRoff might be potentially implemented to silent Tau protein expression implicated in Alzheimer’s disease (AD) development. Thus, preventing the expression of this protein would result in a promising approach to arrest disease progression.
However, CRISPRoff is not yet ready for being such a treatment. Indeed, several questions on this valuable application still need to be answered, as well as, challenges on developing further gene-editing technologies. The possible application of genome-editing technology would definitely represent a valuable approach to treat inherited mutations, such as familial Alzheimer’s disease (FAD). In this regard, scientists at the Hong Kong University of Science and Technology (HKUST) developed a newly genome-editing system able to decrease AD pathology in genetically modified AD mouse models while ameliorating AD pathology across the entire brain. Moreover, it was found that low levels of amyloid accumulation, were maintained for 6 months after the single non-invasive intravenous dose, and no side effects were also reported in mice; a very promising therapeutic strategy for treating and preventing further AD development.
Innovating the way of conducting scientific research, CRISPR became popular while promising a gene-editing method faster, cheaper, and easier than those already implemented to treat so far incurable diseases. However, the understanding of diseases through genome editing and CRISPR-Cas9 is currently based on cells and animal models and scientists are investigating whether this advanced method is safe and efficient when applied to humans, although ethical concerns may arise due to alteration at the human genomes caused by this technology. Nevertheless, we cannot neglect the importance of understanding this technology in modifying biology and possibly treating a variety of complex diseases such as cancer, heart disease, mental illness, human immunodeficiency virus (HIV) infection, or even more, muscular dystrophy, malaria, and Huntington’s disease.
CRISPR: the solution for tomorrow
Having seen how CRISPR was discovered, how it works, and in which medical applications have been already implemented to repair previously unsolved healthcare challenges, which are the perspectives in utilizing CRISPR to unlock future opportunities in humans?
In our latest article series on Supernatural, we will answer this question to foresee innovative and unusual CRISPR solutions impacting the different types of industries into this sci-fi scenario.
From curing HIV and debilitating diseases translating it into new drugs, to genetically modified superplants and allergy-free foods, greener fuels, to pet breeding and ancient animals de-extinction, to editing embryos generating superhero babies or, to extending youth and enhancing brain capabilities, the latest scientific discoveries and planned researches will be considered.
“Jack...why is there a dragon in our backyard?” (Kyoko M., Of Dawn and Embers)
CRISPR/Cas 9 represents the ultimate and most accurate gene-editing method to overcome challenges and limits faced so far in healthcare. However, despite its promising applications opening a wide range of healthcare opportunities, ethical concerns regarding the future of CRISPR applications should not be denied remaining still a topic under discussion.
More on CRISPR/Cas9 applications can be found in the video below:
- Jaenisch, R., & Mintz, B. (1974). Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA. Proceedings of the National Academy of Sciences of the United States of America, 71(4), 1250–1254. https://doi.org/10.1073/pnas.71.4.1250
- Ishino, Y., et al. History of CRISPR-Cas from encounter with a mysterious repeated sequence to genome editing technology. Journal of Bacteriology, 200, 7 (2018). e00580-17. DOI: 10.1128/JB.00580-17.
- van Embden JD, Cave MD, Crawford JT, Dale JW, Eisenach KD, Gicquel B, Hermans P, Martin C, McAdam R, Shinnick TM, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol. 1993 Feb;31(2):406-9. DOI: 10.1128/jcm.31.2.406-409.1993. PMID: 8381814; PMCID: PMC262774.
- Makarova, K.S. et al. A DNA repair system specific for thermophilic Archaea and bacteria predicted by genomic context analysis. Nucleic Acids Research, 30, 2 (2002). 482–496. DOI: 10.1093/nar/30.2.482.
- Mojica, F.J.M. and Rodriguez-Valera, F. (2016), The discovery of CRISPR in archaea and bacteria. FEBS J, 283: 3162-3169. https://doi.org/10.1111/febs.13766
- Li, H., Yang, Y., Hong, W. et al. Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects. Sig Transduct Target Ther 5, 1 (2020). https://doi.org/10.1038/s41392-019-0089-y
- Uddin F, Rudin CM and Sen T (2020) CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front. Oncol. 10:1387. DOI: 10.3389/fonc.2020.01387
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