Genome-Editing Technology Is Unsafe and Unethical in Human Subjects

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Genome-Editing Technology Is Unsafe and Unethical in Human Subjects
Molecular biologists have, in the last decade, been immersed in the process of looking for ways that cellular repair processes can be applied in the quest to modify the DNA of organisms. According to Hsu, Lander, and Zhang (2014); who are all affiliates of the Broad Institute of MIT and Harvard and associate professors of Stem Cell and Regenerative Biology, scientists have been guided by genome editing technology which enables them to change the genome of an organism via the introduction of a new function or correcting an existing mutation.
Rodriguez (2016); a lecturer in Interdisciplinary Center for Studies on Bioethics, University of Chile, states that the last two years have witnessed the emergence of CRISPR-Cas9 as one of the preferred methods for genome editing. One of the reasons for its adoption is its simplicity and precision, high degrees of fidelity (exactness and accuracy of the modified genes), and the low cost and relatively simple construction. Such features have made any molecular biology lab become attracted to CRISPR-Cas9. As such, many molecular biologists have sought to use genome editing to cut off a part of human DNA which is seen as the pathway that certain conditions; such as HIV, use to infect the cells.
The first gene edited embryos occurred in China in 2018 where Dr. He Jiankui edited the genes of the embryos of twin baby girls (Ma, Zhang, & Qin, 2019).

Genome Editing in humans through the use of CRISPR/Cas9 is not entirely perfect as it brings about various safety and ethical issues. The study by Wrigley & Newson (2015); both affiliates of the Centre for Values, Ethics and the Law in Medicine, School of Public Health, University of Sydney, argue that in human germline editing (a deliberate change of genes passed onto children and future generations) using CRISPR-Cas9, gene editing can present serious ethical problems.

For example, the changes made in the germline, as well as the associated risks, are passed down to future generations. Additionally, according to Shinwari, Tanveer, & Khalil (2017); all experts in biotechnology and tenured professors in Quaid-i-Azam University, genome editing presents challenges to human safety and ethics because of its risks of both unforeseen and undesirable effects, especially when applied clinically in the correction or prevention of genetic diseases. For instance, there is the possibility of off-target effects (adverse effects on parts unrelated to the target of interest) as well as mosaicism (two genetically different types of cells).

Additionally, a lack of informed consent; considering those who are affected by the edits are the embryo and future generations (who have not consented to the editing),

makes genome editing not only an unsafe technology but also unethical one. Figure 1 below shows a picture of how genome editing is done to an embryo using CRISPR machinery

Figure 1: An Embryo Being Edited with CRISPR Machinery. This picture demonstrates that CRISPR is a complex process involving technology and science in the development of biotechnology products. Source: Klein and Le Page (2018). Retrieved from on March 29, 2019.

The Context of the Issue
The realm of recombinant DNA technology started to develop in the 1970s with a breakthrough in a new area of biology; genome editing. In specific, molecular biologists gained the ability to manipulate the DNA molecules, study genes, and harness them, with the ultimate aim of developing novelty (modernity) in the realms of medicine and biotechnology (Hsu, Lander, & Zhang, 2014).

However, the recent developments in the area of genome engineering technologies have sparked increased attention for biological researchers. As opposed to the study of DNA which has already been taken out of the realm of genomics, molecular scientists can now edit directly or correct the DNA functional sequences and cause genetic variations (Shinwari, Tanveer, & Khalil, 2017). Clustered regularly interspaced short palindromic repeats (CRISPR) technology was discovered in 1987 and chosen as the primary method of genome editing. However, whereas genome editing technology has been found to have minimal adverse effects on animal subjects, it has raised various ethical issues when used in human beings; such as their safety and consent of future generations (Rodriguez, 2016). In specific, the technology was first used and found useful in editing the genes of many organisms such as insects, plants, fish, bacteria, and even birds and mammals, among others. In dogs, it was found to be effective in fixing muscular dystrophy,

The first time that the genome editing intervention was used for human cells

was in 2018 when Dr. Jiankui He created the world’s first genetically edited babies; twin girls, using CRISPR technology (invented by Feng Zhang among other scientists) (Cyranoski & Ledford, 2018).

The parents of the two girls had were recruited from a group of patients with HIV (see Figure 2 below for a demonstration of how scientists pick out one or more genes for editing).

Figure 2: A visual depiction of tweezers being used to pick out a portion of genetic material for editing. Saey (2018). The diagram demonstrates how scientists can snip out and make a replacement of genes to alter body development. Retrieved from on March 29, 2019.

A vital ethical issue which should be considered in the use of new technology, especially in the realm of healthcare, is the analysis of the risks against the benefits. For example, under Assisted Human Reproduction Act of 2004, editing the human genome is punishable by up to 10 years in prison.

When used in humans, CRISPR/Cas9 has been found to present various risks which outweigh the benefits (Cyranoski & Ledford, 2018).

One of the dangers is that the technology may produce off-target mutations (≥50%)

which have been found even to be deleterious.

In specific, according to Hsu, Lander, and Zhang (2014), studies have demonstrated that CRISPR-Cas9 causes high frequencies (30%) of off-target effects on human cells compared to the ones in both mice and zebrafish. The rising problem, in this case, is that large genomes have the possibility of containing multiple DNA sequences which are highly identical/homologous to the DNA sequences being targeted.

According to Rodriguez (2016), the use of CRISPR/Cas9 cleaves the unintended consequences resulting in mutations which may cause not only transformations of the cells but also their death (see Figure 1 below on how CRISPR/Cas9 works in genome editing).

Wrigley & Newson (2015); both biotechnicians, assert that a high possibility for off-target effects such as the edits ending up in the wrong place as well as some cells carrying the edit and others failing to make the safety of the CRISPR/Cas9 for humans a major concern. As such a need arises for the users of the genome technology in human subjects to weight the benefits of the technology against the risks.

Figure 3: CRISPR-CAS9 gene editing tool.

Source: Fernandez (2018). Retrieved from on March 29, 2019.

Although genome editing has been found to have the benefits of eliminating some disease by preventing them from being transferred into future generations, it has also raised various ethics issues (Rodriguez, 2016). One of the ethical grounds is that of concern for the safety of human subjects. For instance, according to Shinwari, Tanveer, and Khalil (2017) argue that the ethical implications for the use of CRISPR in human genome editing, the high possibility of mosaicism and off-target effects makes the technology not only unsafe but also risky when used in humans. There has been an agreement between researchers as well as scientists that;

before the technology is deemed safe and ethical, it should not be used in the clinical reproductive processes as the risks cannot be used to justify any potential benefits. The other cause of the issue is an aspect of informed consent. In specific, since the CRISPR-Cas9 is used to correct or alter the DNA of the embryo and future generations, then it becomes impossible to obtain informed consent even for use in germline therapy. However, the focus should be on the safety of the technology especially to humans considering that the technology should be used to make lives better as opposed to posing various risks to the subjects.
What, how and why of the Issue

The use of genome editing technology to cut off a specific DNA part which is a pathway to a condition such as HIV and which infects the cells is unsafe because of the risks of off-target mutation and other unforeseen effects. For instance, Zhang et al. (2015);
authors in different areas of biomedicine, established that the use of CRISPR-Cas9 is dangerous for children because it could lead to a gene mutation such as vulnerability to HIV.
The magnitude of this problem can be established from Dr. He, the first scientist to implement the work on the genetically edited embryos who were naturally resistant to HIV (see Figure 2 below for the process of genome editing. )

For example, Belluck (2018); a general surgeon in Devils Lake, ND & Grand Forks,

reports that Dr. He acknowledged that although he did not find any off-target effects, he will continue to track any off-target mutation via the use of blood tests (Belluck, 2018).

Such a statement implies that he is already accepting that a possibility exists whereby the experiment could fail to gain the desired effects and result in the risk of genetic mutation to the embryos. The implications for embryos who are subject to genome editing is that children conceived from such a process will continually be monitored throughout the entire life and would continue to carry some unpredictable risks. Children deserve to live their lives unhindered and not being burdened by risks that cannot be deciphered (Rodriguez, 2016). As such, using genome editing is unsafe and unethical.

Figure 4: how CRISPR works in human genome editing. Source: Gupta and Musunuru (2014).
Genome editing has been opposed by various regulatory bodies including the Council for Responsible Genetics (CRG) and the Canadian Institutes of Health Research (CIHR), because of the risk of off-target mutation that it presents to human subjects. In their position paper, the CRG “strongly oppose[d] the use of germline gene modification in humans” because of not only the ethical but also the scientific and social concerns (CRG, 2019). Since the germline manipulations are based on the assumption that an implicated gene in an identified condition might be easily replaced, changed or supplemented, such a position has its pitfalls. For instance, the biological characteristics/traits are depended on the interactions of different genes. Additionally, the gene activity is affected by the multiple processes which occur both inside an organization as well as its surroundings.

As such, Gupta and Musunuru (2014); professors at Harvard University and experts in Stem Cell and Regenerative Biology, assert that it is impossible for scientists to predict the full effect of modifying or replacing a gene or the traits of people. Additionally, the relationship between the genes and traits has not been well and enough understood; as such, there is no guarantee that gene replacements through changing or eliminating genes of certain conditions may not at the same time alter or delete the traits that were intended to be preserved such as the good ones (Rodriguez, 2016).
Until more animal trials have been conducted to ascertain the safety genome editing, it is vital that the technology is excluded for use in human clinical reproductive purposes. For instance, participants in the International Summit on Human Gene Editing agree that although genome editing has revolutionized how edits are done, it remains unsafe for human beings (The National Academies Press (NAP), 2015). Jin-Soo Kim, a director, and professor in Center for Genome Engineering, Institute for Basic Science, Seoul, South Korea, and a participant in the summit, argued that despite the capabilities that CRISPR-Cas9 has, it is still riddled with deficiencies. Some of these are that it can result in the alterations of the DNA at locations other than the targeted ones which could result in the inactivation of essential genes and subsequently the activation of the cancer-causing genes and eventually chromosomal rearrangements (NAP, 2015).
Embryo editing will require much more scrutiny as the decision to continue using it, despite the various risks, depicts ignorance on the part of the scientists and researchers (Rodriguez, 2016). According to Doudna (2015); a cell and molecular biologist at the University of California, Berkeley, although the use of CRISPR–Cas9 genome editing tool should not be banned entirely as this will prevent any further research on the subject, various measures should be taken to ensure that the risks associated with the technology are mitigated. Additionally, Cyranoski and Ledford (2018); authors of articles on nature and bio-security issues, argue that

the high frequency (≥50) of off-target activity which has been associated with CRISPR-Cas9 as well as induced mutations at sites other than those intended for the target is a significant concern which calls for the scientists to stop using the CRISPR-Cas9 for therapeutic and clinical purposes in humans.

Ma, Zhang, and Qin (2019), professors in Key Laboratory of Human Disease Comparative Medicine, China, view the first genetically gene-edited babies as both an irresponsible and too early practice. The procedure not only violates the human rights of the children but also is an affront to the principles and guidelines in various countries which guide and regulate the experiments on human embryos.
Proponents for the use of genome editing technology, more specifically CRISPR-Cas9, have argued that such a technology is a breakthrough which should be appreciated by all. For instance, according to Belluck (2018), Dr. He felt not only proud but also happy that he had made a discovery which was a breakthrough in human genome editing. Additionally, according to Invest (2014), the gene technologies are “highly efficient, precise, and now cost-effective” means for the generation of human and normal modes of disease. Dr. He argued that with the children that he edited; he did not find any of off-target effects. As such, in the views of many proponents, genome editing should be embraced and not condemned. However, the proponents only seek to examine their self-interests (being the first people to use genome editing technology in humans)

without considering the risks involved in the use of such technologies in humans. For instance, the actions of Dr. He were only meant to confer resistance to HIV through the modification of the CCR5 gene (Büning et al., 2018; a member of European Society of Gene and Cell Therapy). However, the procedure was not only risky but also unnecessary. In specific, it was highly unlikely that the parents (who originally carried HIV) of the two children would have passed the HIV to their children using the standard In Vitro Fertilization (IVF) procedures; where fertilization occurs outside the body. Additionally, the proponents fail to appreciate the importance of observing ethics and weighing the benefits of their undertakings against the risks which they expose the children to after the genome editing (Belluck, 2018).

Figure 5: Dr. He’s representation of what transpired during the human genome editing process. Source: BBC (2018). The diagram represents the steps taken by Dr. He in the editing of embryos of the twin babies. Retrieved from on March 29, 2019.
Conclusions and Recommendations
Human genome editing is still unsafe and risky, and thus more animal trials should be conducted to ascertain the safety of the CRISPR-Cas9 technology. Based on the examination of the research on the use of genomic editing technology on embryos, various recommendations can be adapted to ensure the safety of children as well as the observance of ethical practices. One of the most vital recommended options to continue testing the technology in animals, such as rats; until the off-target effects are established and the safety of the technology ascertained. Notably, research has demonstrated that researchers and scientists have agreed that one of the significant issues of concern in the use of genomic editing in human subjects is the fact that there are various unforeseen and undesirable effects of the technology on children. Some of these include gene mutation such as the possibility of the children being susceptible to other viral infections. As a result, researchers should continue to examine the use of technology in animals and ascertain its safety before they can start to implement it on humans. The self-interests of the scientists and researchers should not overshadow the fact that the technology presents various dangers to children who have to be monitored in the entirety of their lives to establish any off-target effects. Biotechnologists should continue with animal trials to assess the impacts of the genome testing before they can decide to use it on human embryos. Additionally, I recommend that the various ethical issues associated with the technology are addressed. For instance, since the embryos cannot give informed consent, then regulations should be passed in different countries by relevant regulatory bodies on how the approval could be obtained to avoid changing the genes of future generations without consent.

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