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The Ethics Surrounding Genome Editing

What is genome editing?


Genome editing is the modification of any organism’s DNA, such as plants, bacteria and animals. Any known gene can be modified through various technologies, the earliest being developed in the later 1900s. CRISPR is the latest gene editing tool to be developed and is now considered to be the most efficient, low-cost and precise tool available. Genome editing can be done on two different type of cells with different outcomes – on somatic cells, making DNA changes non-heritable, and on germline cells, making them heritable (they will be passed down to offspring!). As somatic and germline genome editing have different outcomes, their regulation will be different based on the ethics surrounding their potential uses and applications.


The ethics surrounding genome editing


Somatic genome editing

Somatic genome editing (SGE) refers to editing the DNA of any cells, except those involved in reproduction, making the DNA changes non-heritable (i.e. they will not be passed down to future generations). The possible clinical applications of SGE mainly encompass the treatment and prevention of human diseases, especially genetically inherited diseases. There are two main types of inherited diseases (diseases passed down parents): autosomal recessive, such as sickle cell disease and cystic fibrosis, and autosomal dominant, such as Huntington’s disease (See Figure 1).

Figure 1: Inheritance of genetic conditions. Autosomal recessive inheritance occurs when two copies of a mutated gene are present in an individual. If an individual has a single copy of the mutated gene, they will usually not show signs or symptoms of the disease. On the other hand, one mutated variant of the gene is sufficient for a person to be affected by an autosomal dominant condition. It can occur due to an affected parent or a new mutation (also known as de novo mutation).


If the application is solely medical, and not for purposes other than the treatment or prevention of a disease (enhancement), SGE could be allowed to treat patients, on the condition that risks are assessed. The improvement of the risk-benefit ratio – the ratio of the risk of treatment or action to its potential benefits – through the improvement of the technique, is essential to allow the application of SGE. In fact, it is the risk-benefit ratio that can determine if such treatment is considered ethical. Currently, a few clinical trials are underway involving CRISPR-based gene therapy focused on leukaemia, HIV-1, sickle cell disease, and others.


Ethicists take two opposing positions regarding SGE; some deny that SGE raises specific or novel challenges (continuity) while others argue that is it unprecedented.


Those supporting continuity claim that SGE with CRISPR-Cas9 in unproblematic as it would not affect an individual’s offspring. The main ethical issues raised by SGE relate to safety assessment, risk-benefit ratio calculation and equity of access. These issues are not novel but like existing ethical issues and challenges addressed within previous debates.


Those that claim SGE is unprecedented question the existing ethical and regulatory frameworks to govern CRISPR-based genome editing. There is lack of coordination among authorities on how to assess clinical utility, safety, and efficacy of CRISPR technologies and patient specific CRISPR therapies might require their own individual approvals. As for any new intervention, questions on risk and safety assessment, informed consent, protection of vulnerable subjects and equity of access are raised, but other questions remain. Are current clinical trials standards and procedures adequate to assess and regulate SGE with CRISPR-Cas9? Will there be a need for special protection of participants? What is the role of commercial companies in developing and offering treatments? They finally claim that it could serve as an opportunity to conduct meaningful engagement, to educate and interchange with relevant stakeholders and to discuss what constitutes as risk or benefit.


Germline genome editing

Germline genome editing (GGE) edits germ cells, thereby inducing heritable DNA modifications. This latter application is more controversial as it raises ethical considerations on the heritability of these modifications to future generations. The ethical debate on GGE started in 2015 when a voluntary moratorium – the voluntary suspension of activities – and a “prudent path forward” were called for. Following He Jiankui’s controversial research, another global moratorium was called to establish an international governance framework.


Basic research with GGE

Basic laboratory (non-clinical) research with genome editing on human embryos could help us better understand developmental biology and genetic diseases while increasing our knowledge of CRISPR technology. It could help us understand early human development mechanisms with the hope of addressing causes of early miscarriages and improving in-vitro fertilisation (IVF), an artificial reproductive technology (ART). Basic research could promote advances for conditions including Parkinson’s disease and cardiomyopathy, which could be ameliorated by regeneration. Some ethicists even argue that conducting genome editing research in human embryos is a “moral imperative”.


Editing the genome of human embryos is controversial, largely due to the lack of clarity on the status of the human embryo. In most countries, the embryo is considered to be less than a full human being but more than a clump of cells. For example, in Switzerland, basic research on embryos is technically allowed by the Federal Council but is restricted to demonstrations of “human dignity” as embryos are due to potentially become a human being. However, in English law, the embryo does not have any rights of its own and only acquires them after birth.


Some scientists deem experimentation on human embryos after 14 days ethically impermissible, but there is no one group that can decide on the status of a human embryo, whether it is the government, a religious group, or a panel of experts. Some have called to extend this 14-day period to study in greater detail embryonic developmental biology. This is displayed in human embryonic research regulation which differs even within countries – for instance, some states in the USA enforce a complete ban, while others support the research. The global legislation landscape on embryonic research is equally divided.


Ethical distinctions on the source of the embryos are drawn by certain scholars; research on supernumerary embryos, usually created during IVF, is considered more ethically acceptable than research on embryos that have been created specifically for this purpose. This is reflected in embryonic research legislature; some countries allow the creation of embryos for research, while others only allow the use of supernumerary embryos in research.


Other issues, including the protection of the women, who supply their egg cells for research, from potential pressure and exploitation, must be addressed in relation to basic research. It also invokes a slippery slope of concerns which proposed that allowing genome editing on human somatic cells or human embryos could lead to future clinical research being regarded as ethically disturbing.


Clinical research with GGE

To assess clinical research with GGE, we will employ the four-principles approach of bioethics, developed by Beauchamp and Childress and often used for decision-making:

  1. Beneficence – the obligation to provide benefits and balance against risks

  2. Non-maleficence – the obligation to avoid negative outcomes or cause harm

  3. Respect for autonomy – the obligation to respect the decision-making capacity of autonomous, independent and self-governing persons (i.e. patients should not be treated without their informed consent)

  4. Justice – the obligation of fairness in the distribution of benefits and risks

The principles of beneficence and non-maleficence are used to criticise and to support interventions with GGE, taking the form of a risk-benefit analysis.


How safe is safe enough” divides stakeholders who must think about:

  1. The potential benefits of CRISPR-Cas9 (beneficence)

  2. Its risks (non-maleficence)

  3. The accessibility to alternatives (justice)

Beneficence

Under the principle of beneficence, the protection of defective embryos or the elimination of diseases that could be eradicated during embryonic development are examples of reasonable arguments in favour of GGE research. Some add that using CRISPR-Cas9 could enable the prevention of genetic diseases through GGE. The medical need is compelling enough, claiming genome editing as a moral imperative to “lighten the burden of human existence”.


GGE could allow prospective parents with the potential of passing down severe conditions to have unaffected and genetically related children. Diseases that could benefit from GGE include Duchenne’s muscular dystrophy (DMD), an X-linked recessive disorder, which manifests around the age of three to five. The degenerative effects are difficult to reverse after the apparition of symptoms, making SGE an inappropriate alternative. DMD affects multiple muscle tissues which SGE cannot treat, but GGE could. If the parents are known carriers of DMD, GGE could be done on an early embryo and only single cells of gametes – the individual haploid sex cells, so the egg or the sperm – or zygotes – the diploid cells formed when two gamete cells join by sexual reproduction – would have to be targeted, making GGE better suited than SGE. Currently, couples can opt to use preimplantation genetic diagnosis (PGD) which allows the selection of embryos that do not carry DMD-causing mutations, or any other monogenic disorders, to avoid having an affected child. Is the desire of these couples convincing enough to justify the introduction of GGE in clinics? Some say that only a small proportion of couples would benefit from it, in rare cases where PGD is not successful, questioning the need for GGE. Some add that genetic relatedness – the percentage of similar genes shared by two persons – should not justify the development of new technologies and does not constitute a reason to allow GGE, and that PGD and GGE are not sufficiently different to consider the latter for clinical applications. Conversely, some in favour of GGE argue that it could be the only option to create unaffected embryos in cases where PGD does not work.


Further developing the slippery slope argument, GGE for clinical research could lead to the enhancement of human features. However, the line between therapy and enhancement is sometimes ambiguous, making the risk-benefit ratio difficult to assess. Although research is still far from being able to edit eye colour or height, as it involves complex genes, we must acknowledge that allowing GGE might lead in the future to research for enhancement purposes.


Non-maleficence

Under the non-maleficence principle, the technical risks of CRISPR-Cas9 limit its clinical applications and should be improved before its use on germ cells, as they could have negative effects on offspring. Some consider GGE as exceptional and unnatural, in line with the naturalism argument which argues that if something is natural it must be good and vice-versa. However, diseases are natural, and millions of humans die every year due to natural causes, making natural phenomena or natural creatures not inherently good. Even natural reproduction is dangerous as only a third of human embryos develop successfully, leading to many miscarriages. GGE could thus reduce the number of miscarriages and the cost of human lives, all the while researching the risks and benefits of genome editing and improving this new technology.


More than 60 ethics statements hold that GGE should currently be prohibited. However, the NASEM report specifies that conditions must be met for GGE research to commence, including “the absence of reasonable alternatives”, “comprehensive plans for long-term, multigenerational follow-up that still respect personal autonomy” and “maximum transparency consistent with patient privacy”.


Respect for autonomy

Respect for autonomy, human dignity and freedom are aspects that must be considered in the GGE ethical debate. The United Nations Educational, Scientific and Cultural Organisation (UNESCO) stands for human dignity and aims to protect the human gene pool as the “heritage of humanity”. GGE could thus threaten the “inherent human dignity” of all human beings. However, it does encourage research that would benefit the humankind, but its results should not be used for non-peaceful purposes, including eugenics.


Future generations cannot give their informed consent on germline interventions, potentially removing their dignity. Yet, prohibiting GGE knowing that it could reduce the frequency of genetic diseases in the future might be a violation of dignity as this intervention could have spared individuals from suffering. Additionally, if GGE becomes trivial in the clinical field, couples might feel forced to have their embryo edited due to social pressure and expectations.


GGE, even if only for medical purposes, might lead to the return of eugenics – practices that have the aim to improve the genetic quality of the human population by eliminating individuals and groups considered inferior and selecting those deemed superior – with precedents such as Buck v. Bell in Virginia, USA, under Justice Oliver Wendell Holmes of the U.S. Supreme Court, involving human beings being forcibly sterilised because they were “feeble-minded”, or the Holocaust, both being backed by state authorities. This could “affect human dignity of entire social groups”.


Justice

GGE could create additional inequalities, contradicting the justice principle. Due to patent rights, CRISPR-Cas9 technology would be costly in the first years, meaning that only those that can afford it would have access to it. However, most of the research on CRISPR-Cas9 has been funded through government grants, which is taxpayers’ money, so why would this technology only be available to the privileged? This could thus bring economic unfairness, although it could be ameliorated by anti-price-gouging laws, which aim to minimise price fluctuation. On the other hand, some argue that this technology could compensate natural inequalities due to the genetic lottery. Yet, it could bring further discrimination to children and adults with genetic disorders and disabilities due to social norm shifts. To address this, the Nuffield Council on Bioethics argued that the use of GGE interventions “should be consistent with social justice and solidarity so that it should not be expected to increase disadvantage, discrimination, or division in society”.


Why should we care about ethics?


We should care about the ethics of genome editing as they can shape the guidelines, regulatory frameworks, and even laws of the use and applications of genome editing. Germline genome editing could enable us to transition from creations to creators, making the role of “God” or genetic randomness obsolete. As this is an important issue that could shape future generations, ethics are more important than ever to guide us through the moral landscape surrounding genome editing.


Author


Emma Balibrea

BSc Biochemistry

Imperial College London


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