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Gene Editing and Ethical Questions for Biomedicine

By Adaobi Rhema Oguejiofor

It is no longer news that technology is rapidly growing and spreading into every sector and endeavour. The medical field is one of those areas where technology is soaring and thriving, with new developments that make saving lives easier springing up every now and then. The desire to solve problems like curing and preventing chronic diseases have led to the deep research and innovation of the Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) Gene Editing Technology, which gives scientists the ability to change an organism’s gene.
The United States of America’s National Library of Medicine (NLM) has described CRISPR or Cas9 as a gene-editing technology that is bringing about a major uproar in biomedical research. This technology creates the possibility of correcting errors in the genome, which is the complete genetic information of either Deoxyribonucleic Acids (DNA) or, in some viruses, Ribonucleic Acid (RNA) of an organism, by removing, adding or altering sections of the DNA/RNA sequence. It turns on or off genes in cells and organisms quickly, cheaply and with relative ease. It is currently the simplest, most versatile and precise method of genetic manipulation at the forefront of research in the world of science.
This technology has the potential to treat genetic disorders caused by single gene mutations and also possesses a number of laboratory applications including rapid generation of cellular and animal models, functional genomic screens and live imaging of the cellular genome.
Research has ascertained that CRISPR/Cas9 can be used to repair defective DNA in mice, thereby curing them of genetic disorders and scientists are still working to determine whether this technology is safe and effective for use in humans. Other potential clinical applications of the innovation include gene therapy, the treatment and prevention of more complex diseases like the Human Immunodeficiency Virus (HIV), cancer, heart disease, and mental illness, among others.
CRISPR-Cas9 was adapted from a naturally occurring genome editing system that bacteria use as an immune defence. These bacteria, when infected with viruses, capture small pieces of the viruses’ DNA and insert them into their own DNA in a particular pattern in order to create segments referred to as CRISPR arrays. The CRISPR arrays allow the bacteria to “remember” the viruses or closely related ones and if the viruses resurface again, the bacteria produce RNA segments from the CRISPR arrays that recognize and attach to specific regions of the viruses’ DNA. The bacteria can then use Cas9 or a similar enzyme to cut the DNA apart, which therefore disables the virus.
This immune defence system was adapted by researchers to edit DNA. They create a small piece of RNA with a short “guide” sequence that attaches and binds to a specific target sequence in a cell’s DNA like the RNA segments bacteria produce from the CRISPR array. This guide RNA also attaches to the Cas9 enzyme and when introduced into cells, it recognizes the intended DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location, mirroring the process in bacteria. Once the DNA is cut, researchers use the cell’s DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.
Quanta Magazine, a scientific online publication, reported that scientists had originally discovered the CRISPR in bacteria in 1987, but at the time, they did not understand the biological significance of the DNA sequences, and it was not yet named CRISPRs. At Osaka University in Japan, a molecular biologist, Yoshizumi Ishino and his colleagues first found out the characteristic nucleotide repeats and spacers (the code bacteria use to remember viruses) in the gut bacteria (microbe Escherichia coli), and as the technology for genetic analysis improved in the 1990s, other researchers found CRISPRs in many other microbes.
A Spanish scientist at the University of Alicante in Spain, Francisco Mojica in the ‘90s, extensively researched that CRISPRs put together a series of repetitive patterns in the DNA of bacteria and archaea. He was the first to describe the distinct characteristics of CRISPRs and he found the sequences in 20 different microbes. At first, he called the sequence “Short Regularly Spaced Repeats” (SRSRs), but he later suggested that they be called CRISPRs instead. The term CRISPR first appeared in a 2002 report, which was published in the journal Molecular Microbiology and authored by Ruud Jansen of Utrecht University.
But in 2012, a professor of biochemistry, biophysics and structural biology at the University of California, Berkeley, Jennifer Doudna and the director of the Max Planck Unit for the Science of Pathogens, Emmanuelle Charpentier took the discovery of this technology a step further and proposed that CRISPR-Cas9 could be used to cut any desired DNA sequence by just providing it with the right template. The two scientists are credited with adapting the bacterial CRISPR/Cas system into a handy gene-editing tool.
In 2013, researchers in the labs of a biochemist Fang Zhang and that of a geneticist, George Church published the first reports describing the use of CRISPR-Cas9 to edit human cells in an experimental setting. The studies conducted in lab dish and animal models of human disease have demonstrated that the technology can effectively correct genetic defects.
A noteworthy factor is that CRISPR is not the first system that enables the editing of DNA in all sorts of organisms. There are other gene-editing technologies, which were used extensively before like TALEN and zinc-finger nucleases (ZFNs). Some experts point out that these tools, have been in use for a sufficient period to become quite refined and they are more accurate than CRISPR-Cas9. However, CRISPR brings an important advantage over all these other techniques as it is much easier and faster to use. Most previous technologies required creating a gene-editing protein from scratch for each specific DNA modification but with CRISPR, the same Cas9 molecule can be directed to any sequence just by providing it with a guide RNA molecule, which is much easier to synthesize.
Life Science, a scientific website, noted that CRISPR technology has been applied in the food and agricultural industries to engineer probiotic cultures and to vaccinate industrial cultures against viruses. It is also being used in crops to improve yield, drought tolerance and nutritional properties.
Another potential application of the technology is to create gene drives, which is a genetic engineering technique that increases the chances of a particular trait passing on from parent to offspring. This kind of genetic engineering derives from a natural phenomenon, where specific versions of genes are more likely to be inherited and according to the Wyss Institute, eventually, over the course of generations, the trait spreads through entire populations.
Concerning the technology’s successes, a BBC News report disclosed that during the COVID-19 pandemic, the CRISPR-Cas9 system was used to develop various diagnostic tests for the viral infection. Similarly, on August 2, 2017, scientists revealed in Nature, a scientific journal, that they had removed a heart disease defect in an embryo successfully using CRISPR. Also, on January 2nd, 2018, researchers announced that they may be able to stop fungi and other problems that threaten chocolate production using CRISPR to make the plants more resistant to disease. According to a research published by the journal BioNews, on April 16, 2018, researchers upgraded CRISPR to edit thousands of genes at once.
However, despite its many successes and uses, the tool is not without its defects. George Church stated that to him, the biggest limitation of CRISPR is that it is not a hundred per cent efficient, which implies that, in a given experiment, the technology may successfully edit only a percentage of the targeted DNA. The technology can also create “off-target effects” when DNA is cut at sites other than the intended target. This can lead to the introduction of unintended mutations. Church noted that even when the system cuts on target, there is a chance of not getting a precise edit. He called this “genome vandalism.”
The many prospective applications of CRISPR technology have raised questions about the ethical merits and consequences of tampering with genes. In general, making genetic modifications to human embryos and reproductive cells, such as sperm and eggs is known as germline editing and since changes to these cells can be passed on to subsequent generations, using CRISPR technology to make germline edits has raised a number of ethical concerns.
Inconsistent effectiveness, off-target effects, and imprecise edits all pose safety risks as there is much that is still unknown to the scientific community. David Baltimore and a group of scientists, ethicists and legal experts in an article published in 2015, noted that germline editing raises the possibility of unintended consequences for future generations because there are limits to the knowledge of human genetics, gene-environment interactions, and the pathways of disease, including the interplay between one disease and other conditions or diseases in the same patient.
Some other ethical questions that have been raised include, should changes that could fundamentally affect future generations be made without having their consent? What if the use of germline editing changes from being a therapeutic tool to an enhancement tool for various human characteristics?
To address these concerns, the National Academies of Sciences, Engineering and Medicine in the United States put together a comprehensive report with guidelines and recommendations for genome editing. Although the Academies urged for caution in pursuing germline editing, they emphasized that caution does not mean “prohibition.” They recommended that germline editing should be done only on genes that lead to serious diseases and only when there are no other reasonable treatment alternatives.
They also stressed the need to collect data on the health risks and benefits, as well as maintain continuous oversight during clinical trials. The Academies recommended that, after a trial is concluded, trial organizers should follow up with the participants’ families for multiple generations in order to see what kind of changes persist in the genome over time.
The future of CRISPR gene editing technology is promising, even though it comes with challenges that need to be addressed. For the future, CRISPR can bring about increased efficiency and specificity. Researchers are constantly improving CRISPR to make it more precise and efficient. New variants of the Cas9 enzymes and guide RNA designs are being developed to minimize unintended edits or off-target effects.
Also, because delivering CRISPR machinery safely and effectively inside cells remains a hurdle, new delivery methods using nanoparticles or viruses are being explored to target specific tissues and organs. Beyond targeting only rare genetic disorders, CRISPR holds promise for more common diseases like heart disease, cancer, and Alzheimer’s. Therefore, research is ongoing to understand the complex genetics of these diseases and develop CRISPR-based therapies.
For the future, ethical considerations remain paramount because germline editing, where changes are made to sperm, egg, or embryo cells, continues to raise ethical concerns. However, International collaborations are underway to develop guidelines and regulations for safe and responsible use of CRISPR.
Overall, CRISPR gene editing has huge potential for revolutionizing medicine, agriculture, and various other fields. However, addressing the technical challenges, navigating ethical considerations, and fostering open communication with the public concerning the development and use of this technology is very important for its successful and responsible advancement.