Genome Editing 101: Ethical Problems in 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

Genome Editing 101: Ethical Problems in Genome Editing

In 2018, the thing that many scientists were very afraid of happened. He Jiankui, an associate professor at the Southern University of Science and Technology in Shenzhen, China, edited the genome of two human embryos that had grown into children. He gained access to these embryos because the parents were involved in an in vitro fertilisation (IVF) pregnancy. He broke a large number of ethical codes and consensuses by editing the genome of human embryos for the first time in history (Krimsky, 2019). He edited a specific gene coding for a co-receptor that plays a role in HIV-infection. Generally, people with a mutation in this gene are more resistant to the virus. His goal was to engineer two babies that would be more resistant to HIV (Greely, 2019). The scientific community was outraged.

He was sentenced to three years in prison as a result of his irresponsible actions and malpractice. Not only was this experimental research on human embryos simply not allowed, but he did his work in secrecy. Neither the parents nor the authorities knew about this highly dangerous research. Though the case remains a mystery, especially since the court of law was held in private, many scientists agree that this study was premature and dangerous (Normile, 2019). All in all, He had been incredibly irresponsible with an enormously powerful tool that may have detrimental side effects. Not only did He put the two children in danger, but he also fed enormous distrust towards gene-editing tools and the scientific community as a whole.

Figure 1: He Jiankui (LeMieux, 2019).

The scientific community as well as the broader public were very like-minded concerning the situation. Authorities, scientists, and media outlets reacted with outrage. The fact that this happened shines new light on CRISPR/Cas9 and similar gene-editing techniques. Surely, there were many significant ethical debates ongoing, but the urgency of the debate had never been shown, not until He uploaded a video explaining his research on YouTube.

Because CRISPR/Cas9 introduced a new area of gene-editing, offering an incredibly powerful tool to change genetic information, this technique specifically was received with much ethical scepticism. These issues are mostly about the usage of the technique, rather than the practical procedures of it. One of the most significant questions is whether it is ethical to use CRISPR/Cas9 on living material, considering that the technique itself is far from perfect. In previous articles of this 101 series, the inaccuracies of CRISPR/Cas9 were highlighted and termed off-targets. Working with this technique may lead to unexpected and undesired mutations at random sites of the human genome, which can lead to dangerous consequences. Therefore, scientists are concerned about whether it is ethically responsible to help prevent a disease in a patient while taking the risk of causing another unknown disease. Luckily, as more research is done on CRISPR/Cas9 and its applications, the technique is improving in accuracy (Lorenzo et al, 2022).

Figure 2: CRISPR/Cas9 often makes errors, or off-targets (Tasan & Zhao, 2017).

Another argument that comes up quite often is that researchers should not “play god” through gene-editing. The idea behind such an argument is that people should not be allowed to manipulate genetic information, perhaps because it is the true foundation of life if that even exists. However, it is important to note that humans have been manipulating DNA for ages. It started with selective breeding, and since the 90s by working with plasmids, transfection, restriction enzymes, and more (Khalil, 2020). Experts have been improving these techniques so that the chance of side effects can be minimised, while their potential becomes increasingly clear. The vast majority of researchers are therefore against banning the use of these techniques. Instead, the crucial matter is often a debate over where to draw the line on what should be allowed and what should not (Locke, 2020).

To this end, the term “designer-baby” was coined a few years ago. If there is no limitation to the extent to which gene-editing tools could be implemented, parents might prefer their baby to have blue eyes or black hair, which is genetically encoded. This concept has been spreading like wildfire as every major media outlet has been publishing on it, and some fictional stories are even based on it. The science-fiction book Genetic Pressure, for example, is a controversial trilogy about designer babies. A popular movie, Gattaca, also deals with this concept, although it predates CRISPR/Cas9 by 15 years (Steynberg, 2023).

Figure 3: Gattaca was a very controversial movie that came out in 1977 (Amazon, 2023).

Despite being pure science-fiction, Gattaca is a piece of interesting work, the story of which takes place in a dystopian world where social status is determined by the extent to which one’s genes have been altered. The “valids” are the elite, i.e., the people with an ideal genome. The ones that have untouched genomes, however, or “in-valids”, are treated as second-class citizens and do not get the same opportunities or status (Greenbaum & Gerstein 2020).

There are already designer-babies roaming this world, at least to some extent. In IVF, embryos are selected based on the presence or absence of certain genes, thereby influencing the traits of children. These genes, however, have medical implications. If an embryo is found to suffer from Down Syndrome, for example, the parents may decide to select another embryo that is relatively more healthy. The difference that CRISPR/Cas9 could theoretically make here is that using such a technique does not only allow selection based on the absence or presence of a gene. Instead, completely different genes may be created, turning brown eyes into green (Pang & Ho, 2016). This is known as eugenics. Given the cost that these techniques would require, inequity in society would be heavily increased (Steynberg, 2023). It is actually very difficult to find scientifically sound information on designer babies, even though so many media outlets have reported on it.

Figure 4: A schematical overview of the definition of eugenics; the self direction of evolution (Knowngenetics, n.d.).

On the other hand, it would be logical to use such techniques in contexts that offer medical advantages only. At first glance, this makes much sense. People would not be able to choose the eye colour or skin tan of their baby, though they would still be able to seek treatment for any genetic disease. But in this case, the question becomes: what exactly is considered a medical advantage? If a person has a gene that makes them more susceptible to breast cancer, but they do not suffer from the disease, would they be allowed to reduce their susceptibility by knocking out this gene? Or if doctors expect a newborn to be less intelligent, would their parents be permitted to change their genes so that their child could have a more rapid learning curve?

An example that illustrates the difficulty of this distinction was theorised by the Russian scientist Denis Rebrikov, who, in an interview, stated he was working on preventing deafness by editing the genome of five embryos. Through his research, he claimed that he would be able to ensure the children would not develop deafness. The renowned Canadian bioethicist Françoise Baylis reacted with outrage, stating that the case was offensive towards the deaf community. After all, within the community, they tend to think of deafness as a variability rather than a disability (CBC Radio, 2019).

Figure 5: The image that many people have of designer babies (csStanford, n.d.).

The scientific community has not yet been able to draw up any proper approach to deal with gene-editing tools in the future. The call for international organisations that help reach a consensus is growing, however, while the views of some experts are becoming more extreme. This is one of the main subjects of the book, The Code Breaker, co-written by renowned biochemist Jennifer Doudna. Doudna is recognised as one of the founders of CRISPR/Cas9, and she has been trying to raise public attention on this issue ever since she published her first works on CRISPR/Cas9. She has been going out of her way to educate people and stimulate international debates on the ethical issues brought up by this technique. So far, however, the international cooperation she seeks has not been found.

Going back to the movie Gattaca, the science behind its writing is not very detailed, but the picture it paints is very much so. It is a warning of the very slippery slope mentioned earlier: “What began as a means to rid society of inheritable diseases has become a way to design your offspring”. (Greenbaum & Gerstein 2022). Although medical applications underlie the motivation to work with gene-editing tools, in the movie it has become an ability to make virtual super-humans, discriminating against anyone who is otherwise. From the rapid development of these tools, it is not difficult to visualise socio-economic inequality in the near future as a consequence of gene-editing. The novelty of the technique makes it inevitably expensive. Therefore, it is unlikely that people in developing countries will have the same opportunities as those in richer countries. This inequality is already coming about, given the geographical distribution of research on CRISPR/Cas9. There is good news, however, as history has shown that technological advances very quickly reduce in price.

Figure 6: Global distribution of CRISPR/Cas9 research. It is evident that richer countries invest significantly more in this branch of science (Meyer & Vergnaud, 2021).

As stated earlier, scientifically sound information on these ethical issues is difficult to find. What many researchers do point out though, is that scientists do not yet understand everything about DNA. In other words, the dystopian world of Gattaca seems far away. In an interview with Penn Today, a paper by the University of Pennsylvania, PIK Professor Jonathan Moreno even states that designer babies will never really be a reality because the way that DNA encodes physical traits is very complex (Berger, 2018). This has to do with a field of biology called epigenetics.

Epi, in epigenetics, is a Greek prefix that means “above”. Epigenetics, therefore, translates into a layer that is above, or rather, an addition to common genetics. Through the addition of small molecules including methyl, ethyl, and many others, genes can be turned on or off. There are many different kinds of such epigenetic marks, and each means something different depending on their location and structure. Epigenetics has been studied for a number of decades now, but it is far from being fully understood. What is understood at this point, however, is that the DNA sequence does not determine everything in a cell or an organism. Instead, epigenetics plays a large role. This is also why fraternal twins still look different from one another. They have the same DNA sequence, but a different epigenetic makeup. At this point in time, CRISPR/Cas9 is not able to adjust or induce a certain epigenetic structure. It is questionable whether it, or other techniques, will improve to a point where they can do so in the future. Professor Moreno was therefore suggesting that CRISPR/Cas9 can be used to modify certain sequences in the DNA to generate a desired effect, but he believes complex traits encoded by long sequences of DNA still rely heavily on epigenetic make-up and thus could not be manipulated through conventional gene-editing (Deans, 2015).

Figure 7: The DNA sequence does not say everything. Epigenetics are also important (Genomics Education Programme, n.d.).

All these ethical questions merely form a small portion of the unanswered questions posed by bioethicists since the first publications of CRISPR/Cas9. Society, and scientific researchers specifically, have been learning more about the use and the context of such techniques. As a result, people are actively occupied with these ethical issues, and so opinions start to form. Experts have begun to recognise the importance of public opinion on these topics. There is a growing need for politics and the general public to start taking gene-editing seriously and think about its implications in greater depth. Moreover, legislation should be implemented to enable more robust research, but at the same time draw clear lines on what is ethically responsible and what is not. Only by improving our understanding of these techniques will we be able to know what is safe and what the potential dangers are.

To increase public engagement, scientists call for more effort to be put into communication from scientific institutions and agencies. Institutions with much authority, such as the World Health Organisation (WHO), should stimulate and initiate debates about the possible advantages as well as dangers of gene-editing. By doing so, irrational fear of gene-editing will slowly but surely decrease, as people begin to understand why tools like CRISPR/Cas9 can help humanity in battles against diseases, global hunger, and many others.

Figure 8: Jennifer Doudna at her famous Ted Talk in 2015. Here, she expressed the wish for public debate on CRISPR/Cas9 (Nisbet, 2018).

The shocking study by He not only demonstrated the ethical dilemma faced by modern gene-editing, but also revealed to the public that not all scientists can deal with the responsibility of such a powerful technique. The damage done by He is enormous as many people have now become afraid that gene editing may be used to the wrong ends. Luckily, many studies are being conducted, both with CRISPR and with even newer techniques. Many of these show promising applications of gene editing in medicine, as well as in the food industry. Hopefully, not long in the future, scientists can improve the openness of their work and become more willing to participate in ethical debates, rather than crossing boundaries behind closed doors.

Bibliographical References

Berger, M., W. (2018). Thoughts From a MEdical Ethicist on Gene Editing Babies. https://penntoday.upenn.edu/news/thoughts-medical-ethicist-gene-editing-babies

CBC Radio. (2019). Canadian Bioethicist Calls Plan to Prevent deafness in Gene-edited Babies ‘Offensive’. https://www.cbc.ca/radio/asithappens/as-it-happens-tuesday-edition-1.5205193/canadian-bioethicist-calls-plan-to-prevent-deafness-in-gene-edited-babies-offensive-1.5205195

Deans, C., & Maggert, K. (2015). What do you mean, "epigenetic"?. Genetics, 199(4), 887-896. https://doi.org/10.1534/genetics.114.173492

Greely, H. (2019). CRISPR babies: human germline genome editing in the 'He Jiankui affair'. Journal of Law and the Biosciences, 6(1), 111-183. https://doi.org/10.1093/jlb/lsz010

Greenbaum, D., Gerstein, M. (2022). GATTACA is still pertinent 25 years later. Nature Genetics, 54(12), 1758-1760. https://doi.org/10.1038/s41588-022-01242-5

Krimsky, S. (2019). Ten ways in which He Jiankui violated ethics. Nature Biotechnology, 37(1), 19-20.

Khalil, A. (2020). The genome editing revolution: review. Journal of Genetic Engineering and Biotechnology, 18(1), 68. https://doi.org/10.1186/s43141-020-00078-y

Locke, L. (2020). The promise of CRISPR for human germline editing and the perils of "playing god". The CRISPR Journal, 3(1), 27-31. https://doi.org/10.1089/crispr.2019.0033

Lorenzo, D., Esquerda, M., Palau, F., & Cambra, F. (2022). Ethics and genomic editing using the CRISPR-Cas9 technique: challenges and conflicts. NanoEthics, 16(3), 313-321. https://doi.org/10.1007/s11569-022-00425-y

Normile, D. (2019). Chinese Scientist Who Produced Genetically Altered Babies Sentenced to 3 Years in Jail. https://www-science-org.are.uab.cat/content/article/chinese-scientist-who-produced-genetically-altered-babies-sentenced-3-years-jail

Pang, R., Ho, P. (2016). Designer babies. Obstetrics, Gynaecology & Reproductive Medicine, 26(2), 59-60. https://doi.org/10.1016/j.ogrm.2015.11.011

Steynberg, R. (2023). Designer babies: evaluating the ethics of human gene editing. Newcomb College Institute of Undergraduate Research, 7(1).

Visual Sources