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Eprs Stu (2022) 729506 en
Eprs Stu (2022) 729506 en
editing in
humans
A survey of law,
regulation and
governance
principles
STUDY
Panel for the Future of Science and Technology
AUTHORS
This study has been written by Ana Nordberg, Associate Professor at the Faculty of Law, Lund University, and
Luisa Antunes, Policy Analyst at the Scientific Foresight Unit (STOA), at the request of the Panel for the Future
of Science and Technology (STOA) and managed by the Scientific Foresight Unit, within the Directorate-
General for Parliamentary Research Services (EPRS) of the Secretariat of the European Parliament.
ADMINISTRATOR RESPONSIBLE
LINGUISTIC VERSION
Original: EN
This document is prepared for, and addressed to, the Members and staff of the European Parliament as
background material to assist them in their parliamentary work. The content of the document is the sole
responsibility of its author(s) and any opinions expressed herein should not be taken to represent an official
position of the Parliament.
Reproduction and translation for non-commercial purposes are authorised, provided the source is
acknowledged and the European Parliament is given prior notice and sent a copy.
PE 729.506
ISBN: 978-92-846-9455-6
doi:10.2861/07058
QA-07-22-327-EN-N
Executive summary
Genome editing is a powerful new tool allowing precise alterations in the genome. The
development of new approaches based on the CRISPR-Cas9 system has made this process much
more efficient, flexible and affordable, relative to previous strategies.
These technological advances originated in remarkable interest in possible applications, both in
fundamental research and in the treatment or prevention of disease and disability. Possibilities
range from restoring normal function in diseased organs by editing somatic cells to preventing
genetic diseases in future children and their descendants by editing the human germline.
As with other medical breakthroughs, each such application comes with its own set of risks, benefits,
ethical issues and societal implications, which may require the revision of existing regulatory
frameworks. Important questions raised include how to balance potential benefits against
unintended harms, how to govern the use of these technologies, how to incorporate societal values
into relevant clinical and policy applications, and how to respect the inevitable cultural specificities
that shape the future direction of the use of these technologies.
The goal of this study was therefore to provide an overview of the state-of-the-art of the science, as
well as an analysis of current and projected regulatory, ethical, legal and social implications. Based
on these findings, policy options were provided.
The internal market for health and 'wellness' services and products can and is already subject to
considerable harmonisation in the European Union. Provided that there is sufficient consensus,
there is ample room to either introduce genome editing-related provisions in existing directives and
regulations (vertical approach), or to enact specific genome-editing legislation (horizontal
approach). Besides legislative intervention, it is also possible to explore alternative or cumulative
public and private governance mechanisms.
Harmonised definitions would be beneficial to the internal market for health and wellness services
and products. These facilitate legal certainty in the internal market, improving the prospects for
citizens (as patients and consumers), companies and healthcare providers (public or private) to
navigate the different national rules and a fragmented legal landscape. Uniform definitions facilitate
comparison and organic approximation of national legislation, policies, and governance structures.
Legal definitions should include appropriate resilience mechanisms to ensure sustained
correspondence with scientific knowledge. From a regulatory perspective, the use of qualifiers such
as 'somatic versus germline', 'hereditable' genome editing, or 'modifying genetic identity', is
considered scientifically outdated, vague and prone to differing legal interpretations. Somatic as
well as germline applications may carry associated dangers. Once clinical safety is established,
germline interventions could also have strong therapeutic potential. Possible horizontal
harmonisation approaches could include, for example, maintaining a general prohibition, in which
the clinical risk-benefit ratio is unacceptable and, additionally, clarifying concepts and, most
importantly, creating exceptions for research and future treatments of serious diseases.
Regarding genetic eugenics prohibited by Article 3 of the EU Charter of Fundamental Rights, this
study proposes the option of regulation to expressly clarify or extend the prohibition to the actions
of private actors and to somatic interventions where these cannot be considered to be the result of
informed and free consent, and simultaneously clearly exempting preventive and precision
medicine.
Regarding advanced therapeutic product regulation, genome-editing products are currently
subject to a centralised approval procedure, but exceptions are decided locally. One option would
be to further harmonise exceptions granting patients early access, e.g. compassionate use, named-
patient use and hospital exceptions.
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As for genome editing in assisted reproduction techniques, rules and proposals to allow editing are
often linked with the treatment of serious diseases. There is an urgent need to define and, if possible
harmonise science-based criteria used to determine the seriousness of a given disease, including
both from a patient-centric perspective and using medical diagnosis elements.
Uncontrolled somatic editing can pose great social and ethical risks (e.g., inequality, public health
problems, interventions in children and people unable to consent, discrimination, etc.). Regarding
wellness and cosmetic somatic editing (including enhancement), strict regulatory framework for
market approval only applies to products used for the treatment, prevention or diagnosis of a
disease. The use of 'human enhancement' as a criterion for unacceptable interventions is not useful,
as it is too vague, value-charged and difficult to enforce. An option would be to ensure public health
prevention by determining types of editing that should be prohibited or restricted, practitioners'
professional qualifications, safety and technical requirements. Also here, a multi-level, risk-based
approach would allow specific rules to be defined for prohibited and high-risk genome-editing
interventions. Possible criteria could include the objectives of the intervention, expected outcomes
and levels of risk for individuals and society.
Regarding medical/reproductive travel and beauty/wellness tourism, some countries have more
permissive legislation or lack the ability to enforce rules. Restrictions should not hamper access to
experimental or recently approved therapeutic options, including the participation in clinical trials.
Possible options include the extraterritorial application of EU and Member State law to procedures
performed abroad (provided that fundamental rights and freedoms are respected).
As for enforcement and forensic activities, the enforcement of prohibitions needs to account for
fundamental rights and freedoms. An option would be to balance the needs for prevention and
reintegration relating to the specific illicit conduct with the legal rights, interest and well-being of
the victim. Secondly, subjects of illicit genome editing could be treated as victims and could be
specifically allowed to refuse privacy or forensic activities invasive to their physical integrity. The
long-term monitoring and inclusion in registries must also respect the rights to privacy, family life,
personal integrity and autonomy.
Counterfeited or falsified services and products are a known intellectual property rights (IPR) and a
public health issue. Genome editing could be included in the sphere of measures included when
tackling this problem. Private governance through technology-licensing agreements already plays
an important governance role. This study identifies an option to develop general guidance or model
clauses for ethical licensing. The use of artificial intelligence (AI) systems for genome editing is a
future area of concern and should be the object of consideration in AI-related regulation.
In conclusion, this study shows that while genome editing is the source of great expectations for the
medical field, several ethical, social and legal questions remain to be addressed. Regulatory and
governance mechanisms are greatly needed in the EU.
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Table of contents
List of abbreviations _______________________________________________________________ VI
Part II: Principles to guide the governance of human genome editing ________________________ 7
1. Introduction ___________________________________________________________________ 7
2. Methodology __________________________________________________________________ 7
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STOA | Panel for the Future of Science and Technology
2.2. Survey of existing relevant legislation at the EU and international level __________________ 8
3.1. Narratives, metaphors, concepts, and their use for regulatory purposes __________________ 9
3.7. Ethics dumping in research and cross-border procurement of health and wellness services _ 12
3.9. Rule of law, legal, regulatory and governance pluralism and coherence _________________ 14
4.2. WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight
of Human Genome Editing Report __________________________________________________ 17
4.4. European Group on Ethics in Science and New Technologies (EGE) Opinion ______________ 21
UNESCO's Universal Declaration on the Human Genome and Human Rights ___________ 24
The IBC Report on the Human Genome and Human Rights _________________________ 27
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Clinical trials and market approval of medicinal products for human use ______________ 32
EU Member States that signed and ratified the Oviedo Convention __________________ 35
EU Member States that have signed but not yet ratified the Oviedo Convention ________ 37
European countries that have not signed the Oviedo Convention ___________________ 38
8. Conclusions___________________________________________________________________ 44
References _____________________________________________________________________ 47
Annex _________________________________________________________________________ 60
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List of abbreviations
Acr anti-CRISPR
AI artificial intelligence
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Genome editing in humans
The CRISPR-Cas9 system has revolutionised the field of genome editing ever since its discovery in
2012. These 'genetic scissors' are easier to engineer, more efficient in methodology and more precise
in the genome sequence being targeted. Its advantages over previous genetic engineering systems
became so evident in such a short amount of time that, less than 10 years after its discovery,
researchers Emmanuelle Charpentier and Jennifer A. Doudna had received the 2020 Nobel Prize in
Chemistry 'for the development of a method for genome editing' (The Nobel Prize, 2020).
1-The first step in the engineering process is the artificial design of the specific RNA sequence (single
guide RNA, or sgRNA) that will recognise the specific target DNA in the human cell. This step can be
designed by a researcher on any normal computer using bioinformatics software.
2-Then, the CRISPR system must be delivered to human cells, which can be done via lipofection,
injection or electroporation (van der Oost et al, 2016).
3-Once inside the target human cell, the guide RNA will recognise and bind to the target DNA
sequence the researcher wants to modify.
4-Then, the Cas9 protein will cleave the DNA at the chosen location.
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5-As a final step, the natural DNA repair mechanisms of the human cell will help replace the previous
DNA with the new version.
For more information on the mode of functioning of the CRISPR-Cas9 system, please see STOA
publication 'Genome edited crops and 21st century food systems challenges'.
Other systems
Roughly around the same time Jennifer Doudna and Emmanuelle Charpentier designed the
synthetic RNA of the CRISPR-Cas9 technology, Feng Zhang optimised protein Cas9 for in vivo use.
His team has since isolated proteins Cas12 and Cas13 (Yan, Wang & Zhang, 2019) from two bacterial
strains. These show certain technical advantages over Cas9, namely, the ability to perform multiplex
genome editing (Cas12), increasing specificity and thus lowering the possibility of off-target effects
(Paul & Montoya, 2020), and the ability to cleave RNA instead of DNA (Cas13), thus allowing for more
specific modulation of protein-production levels (King-Jones et al, 2020), although being more
susceptible to off-target effects compared to Cas9.
Several fields can potentially be revolutionised by the CRISPR-Cas technology, ranging from
biological research, research and development, human medicine, biotechnology and agriculture.
An example is the dairy industry, where CRISPR-Cas9 is already used to immunise lactic acid bacteria
against phages.
CRISPR-Cas9 can also be used as an alternative to animal testing, as it is faster and less expensive
than traditional animal testing, thus providing faster development of pharmaceutical products. Cells
and organisms that have been engineered using CRISPR-Cas9 include cell lines and model
organisms used in biological research (mice and rats, fruit flies, nematodes, Arabidopsis,
salamanders, frogs, monkeys); crop plants (rice, wheat, sorghum and tobacco) and fungi
(Kluyveromyces, Chlamydomonas) in biotechnology, and organoids, human embryonic stem cells
(hESCs) and induced pluripotent stem cells (iPSCs) in the field of biomedicine (Doudna &
Charpentier, 2014).
However, policy makers have shown concern over the indiscriminate use of this technology in
human health applications and potential ethical and legal issues. The risks and potentials of this
technology have not been thoroughly assessed.
Basic research
Basic research involving genome editing of human cells and tissues is critical to the advancement
of biomedical science. Genome editing research using somatic cells can advance the understanding
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of molecular processes that control disease development and progression, potentially facilitating
the ability to develop better interventions for affected people. Laboratory research involving
genome editing of germline cells can help in understanding human development and fertility,
thereby supporting advances in such areas as regenerative medicine and fertility treatment.
Somatic interventions
Somatic cells are all those present in the tissues of the body except for sperm and egg cells and their
precursors. This means that the effects of genome editing of somatic cells are limited to the treated
individuals and are not inherited by their offspring. The idea of making genetic changes to somatic
cells—referred to as 'gene therapy'—is not new, and genome editing for somatic applications would
be similar. Besides treatment of rare Mendelian-inherited diseases (single-gene diseases) that affect
one main organ or tissue, several countries (e.g. China, USA) have already started clinical trials for
untreatable cancer conditions in human patients. In addition, potential treatments for difficult-to-
treat infectious diseases are underway.
Germline interventions
Although editing of an individual's germline (reproductive cells) has been achieved in animals, there
are major technical challenges to be addressed in developing this technology for safe and
predictable use in humans. The most relevant technical issues relate to the uncertainty resulting
from the cell-dependent DNA repair processes triggered by the double-strand break lesion caused
by the CRISPR system. Up to now, there is no absolute control of the outcome. Many different alleles
can be generated from a single CRISPR intervention and organisms become mosaics, since they
carry cells with different sequences in the target DNA. Nonetheless, the technology is of interest
because thousands of inherited diseases are caused by mutations in single genes. Thus, editing the
germline cells of individuals who carry these mutations could allow them to have genetically-related
children without the risk of passing on these conditions. Yet, the technique must be either devised
so that the organism (the patient) can tolerate the presence of different alleles, or else, must be
optimised until it is fully under control.
Elective interventions
Although much of the current discussion around genome editing focuses on how these
technologies can be used to treat or prevent disease and disability, some aspects of the public
debate concern other purposes, such as the possibility to enhance traits and capacities beyond
levels considered typical of adequate health. In theory, genome editing for such enhancement
purposes could involve both somatic and germline cells. Such technological uses raise questions of
fairness, social norms, personal autonomy and the role of public and private governance.
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Current CRISPR-Cas technology applied to cancer research has shown efficacy in blocking bladder
cancer cell proliferation and in inducing apoptosis. In addition, it was possible to delete an entire
gene responsible for causing myeloid cell leukaemia (Liu et al, 2014). Thirdly, cyclin-dependent
kinases (KDKs), which regulate our cell cycles and whose malfunctioning can often lead to cancer,
could be silenced by CRISPR-Cas in the treatment of osteosarcoma and breast cancer. Challenges
still to be tackled include limiting off-target effects and increasing efficacy and delivery methods
(Chen et al, 2020).
Cystic fibrosis
Cystic fibrosis is a debilitating genetic disease affecting 70 000 people worldwide. It is caused by one
or several mutations in the transmembrane regulator gene CFTR, making it the most common
autosomal recessive disease in Europe. A body of research has gone into studying a possible cure, so
far with limited results. Gene therapy using either zinc-finger nucleases or CRISPR-Cas has allowed
copying the health copy of the CFTR gene from into target human cells (Crane et al, 2015; Sharma et
al, 2021). A newer study has used the primer editing technique, a newer version of CRISPR-Cas9
where Cas9 is fused to a reverse transcriptase, to correct CFTR mutations in human stem cells. This
technique is arguably safer than CRISPR-Cas9 due to completely eliminating off-target effects
(Maarten et al, 2021). However, results have so far been discouraging, due to the low efficacy of gene
delivery into target cells and lack of studies on cell delivery altogether.
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Most of this potential comes from the discovery of two new Cas proteins: Cas12 and Cas13, and
several detection assays have since been developed based on either Cas12 or Cas13 use (Zhan, Li &
Yin, 2021). A CRISPR-Cas13 system can detect the presence of specific viral RNA: it can detect SARS-
CoV-2 presence within 1 hour, with no special instrumentation and with extremely high sensitivity
(Zhang et al, 2020). A CRISPR-Cas12 system can detect the presence of SARS-CoV-2 within
30 minutes, but is less sensitive (3x-7x less) than CRISPR-Cas12.
Aside from advantages as diagnostic tool, Cas12 and Cas13 can also be used as therapeutic option.
In particular, Cas13 has RNA-guided RNA endonuclease activity and thus can degrade specific Covid-
19 RNA (PAC-MAN system) (Safari et al, 2021). The second advantage of this system is its adaptability
to treat all coronaviruses in a single shot, by targeting conserved sequences. An injection of 6
different RNA sequences could target virtually 90% of all coronaviruses (Abbott et al, 2020).
Nevertheless, this study has so far been limited to bioinformatics, therefore, the efficacy of the PC-
MAN system must still be tested in vivo, namely in what regards delivery systems.
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Off-target effects are such as the generation of unwanted mutations via insertion and deletion
(indel) events in unspecific locations in the genome, which can also can increase cell toxicity.
Subsequent exploration of the technique should reduce off-target events and increase specificity.
One possibility to minimise off-target events is the use of algorithmic tools during the design of the
optimal sgRNA molecule (Doudna & Charpentier, 2014). Toxicity could be reduced by using use anti-
CRISPR (Acr) proteins. These are protein inhibitors of CRISPR-Cas systems, naturally occurring in
plasmids and phages (Marino et al, 2020), which act by inhibiting either DNA binding or DNA
cleavage.
3.3. Efficiency
Other challenges of the CRISPR-Cas technique involve editing efficiency, which varies according to
cell type and state. Possible solutions are changes in the plasmid vector, improvement of delivery
systems and cellular uptake, limitation of product degradation, improvement of fitness of edited
cells and immunogenic effects of Cas9.
Immunogenic effects are an important factor for efficiency. Possible solutions are finding less
immunogenic delivery methods, or designing improved, less immunogenic, versions of Cas9.
As for delivery efficiency, technical options for improvement include improvements in viral vectors
or use of non-viral vectors (Cheng et al, 2020).
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2. Methodology
The present report aim is to provide a critical contextual legal analysis and comparison of different
legislative and regulatory approaches to human genome editing. It includes an overview of
international, European and EU frameworks and legislation applicable to human genome editing,
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also comparing approaches to genome editing in selected EU Member States and the UK. It
discusses legal, ethical and social issues surrounding human genome editing and whether these
currently have or lack clear and harmonised solutions.
The methodology includes the following:
• Literature review on ethical, legal and social implications of genome editing;
• Survey of existing relevant legislation at the EU and international level;
• Legal interpretation methods relevant for the jurisdictions surveyed.
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sufficiently general and abstract to ensure respect for equality of treatment, and sufficiently clear
and determinable to respect the principle of legality and legal certainty (Nordberg, 2017).
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& Singer, 2019). However, this principle of procreative beneficence has been opposed (Bennett
2009; Parker, 2005 and 2007) and even the use of assisted reproduction technologies to de-select
disability as for long been criticised (Buchanan 1996; Parens & Ash 2000).
There is general agreement that there is need for a broader societal debate on human genome
editing. However, recent calls for greater inclusion of the disability community perspectives in
genome editing debates (Boardman 2020a) have also been partially meet with counterarguments
focusing not only on beneficence but the protection of the human dignity of the disabled embryo
(de Miguel Beriain, 2020; cfr. Boardman, 2020b).
Notwithstanding, it remains well known in legal circles that medicalisation of personal traits and
identities can lead to various forms of discrimination (being sexual orientation a clear example).
Medical classifications concerning disease and disability and related legal determinations are fluid
having changed considerably in recent history. Meaning that such determinations are not
necessarily immune to context and the availability of new genome editing possibilities is part of
such context (see also Feeney, & Rakić, 2021).
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decade, since currently there are hundreds of gene therapy clinical trials ongoing (High, 2020; Adair
et al., 2021).
There are known problems with equitable access to medicines, in particular in ground-breaking
pharmaceuticals and medical technology. Given the huge potential of genome editing technologies
for curing or preventing diseases that so far have no available treatment, the prevalence of patented
technology in the field and ongoing extensive litigation over such patents (Sherkow, 2018), access
issues such as exorbitant high pricing are already a reality.
Costs of approved gene therapy treatments, range from USD 373 000 to USD 2.1 million (Adair et al,
2021). Despite industry funded studies claiming that a price tag of USD 2.125 million for the one-
time gene therapy for spinal muscular atrophy onesamnogen abeparvobek (Zolgensma - Novartis)
justifiably reflects the cost of innovation (Dean et al., 2021; Garrison et al., 2021), the barriers to
access are evident are clearly linked to the existing incentive structures and regulatory mechanisms
applicable to the pharmaceutical industry.
As the Myriad/BRCA-gene patent (breast cancer diagnosis) commercialisation controversy teaches
us (Association for Molecular Pathology v. Myriad Genetics, Inc., 569 US 576; Lai, 2015), excessive
optimism towards voluntary responsible industry responses to the need for equitable access may
lead to disappointing outcomes (Feeney, 2019). There is a growing global need to consider
alternatives to patents or additional incentive mechanisms, as well as eventual judicial or even
legislative intervention concerning patentability, patent validity and governance principles and
structures to foster responsible marketing practices in the pharmaceutical and biomedicine sector.
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Some countries may either have lack of regulation and other governance mechanisms or reduced
ability to enforce existing rules (Baylis et al., 2020). In other countries, commentators argue that the
explanation resides in internal or external crisis pushing other more urgent issues into the political
agenda, as or example Ukraine were there are reported cases of a clinic planning to offer genome
editing for enhancement purposes (Knoepfler, 2021). It has also been theorised that in some cases,
maintaining ambiguous or permissive regulations could be part of a deliberate political decision
(Schroeder et al., 2019) due to a variety of geopolitical and economic interests in research and
innovation in genome editing and in maintaining a lucrative medical tourism industry.
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3.10. Conclusion
Literary sources analysed offer a vibrant variety of academic discussions, perspectives, and opinions
on the ethical, legal and social implications of genome editing. There is an observed tendency for
sources to concentrate around topics related to human germline or hereditary genome editing. A
noticeable number of publications are devoted to examining how and to what extent prohibitions
of eugenics should be enacted, reformed and enforced. This is more acutely visible, in the contexts
of assisted reproductive technologies and human enhancement. Opinions range from libertarian
and techno-optimistic views on human genome editing as a vector for promoting well-being and
moral and physical improvement of humanity, to bio-conservative, human nature inviolability
ontological considerations and precautionary approaches to technology. In the middle of the
spectrum a broad range of concerns are found, often framed by specific needs of a given group (e.g.
disability) and challenges requiring special attention (e.g. accessibility).
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possible, but this technological advance opened the door to new technological possibilities and
applications.
In April 2015, Chinese scientists announced the use of gene-editing technology (Liang et al., 2015).
The authors of the study stressed that the experiments were conducted in unviable, not intended
to be implanted, human embryos and concluded that there was a need to further improve the
fidelity and specificity of the CRISPR-Cas9 tool before any clinical applications. The announcement
of this research, prohibited in many jurisdictions, was a wakeup call and sparked strong reactions in
the scientific community. Soon after, two distinct groups of prominent scientists proposed a
worldwide voluntary moratorium on germline genome editing in humans as 'an effective way to
discourage human germline modification and raise public awareness' (Lanphier et al., 2015) and a
way to prevent such activities in 'those countries with lax jurisdictions where it might be permitted
[…], while societal, environmental, and ethical implications of such activity are discussed among
scientific and governmental organisations' (Baltimore et al., 2015).
In Europe, national ethics councils assume a leading role in the debate human genome editing
governance of debate. Early on, several ethics councils called for international regulation and
warned about the need to include ethical principles (see below section 5.3). The European
Academies Science Advisory Council, issued a report addressing both human, plant and animal
genome editing (ESAC, 2017).
While in the USA, the Committee on Human Gene Editing: Scientific, Medical, and Ethical
Considerations (established by the National Academy of Sciences; National Academy of Medicine;
and National Academies of Sciences, Engineering, and Medicine) published a preliminary report on
human genome editing concluding inter alia that 'heritable germline genome editing trials must be
approached with caution, but caution does not mean they must be prohibited' (NASEM, 2017).
Despite the early warnings, the scientific community was still taken by surprise and shocked when
on 25 November 2018, He Jiankui, then a researcher in China, publicly announced he had employed
CRISPR-Cas9 technology to edit embryos and that the first genome-edited twin babies had been
born (Cyranoski & Ledford, 2018; Lovell-Badge, 2019). Since then, rumours of an eventual future
support from public institutions in Russia have raised the fear of more such experiences
(Kravchenko, 2019).
The announcement of He's experiment immediately led to a storm of criticism in the international
scientific, bioethics and legal scholars' community (Charo, 2019; Krimsky 2019; Kleiderman &
Ogbogu, 2019; Greely, 2019). Shortly after, scientists, ethicists and legal scholars called for a global
observatory on genome editing (Jasanoff & Hurlbut 2018), which was widely supported by the
academic community.
A joint statement by the Nuffield Council on Bioethics, the German Ethics Council and the French
National Advisory Committee on Ethics in life sciences and health on the ethics of heritable human
genome editing called on 'all jurisdictions to bring heritable genome editing unambiguously within
the control of relevant public authorities and to make its abuse subject to appropriate sanction'
(Bioethics Councils, 2020). While The National Academy of Sciences, Engineering, and Medicine
(NASEM), the Chinese Academies of Science, and the Royal Society of the United Kingdom ('the
Academies') assembled a commission tasked with developing a framework for the assessment of
potential clinical applications of human germline editing.
Also, in the aftermath of this unethical experiment with human germline editing, the World Health
Organisation (WHO) established an Expert Advisory Committee on Developing Global Standards for
Governance and Oversight of Human Genome Editing. The mandate of the WHO Expert Advisory
Committee was broader than the Academies scientific group, since it included governance issues of
all types of human genome editing, including somatic/non-heritable.
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This section presents an overview analysis of these reports and opinions addressing the ethics and
governance of human genome editing, with a view to identify commonalities, divergences and
guiding principles for legal and regulatory interventions, which will be presented in sections 7 and
8.
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destruction of a 'significant cohort of edited human embryos' (Annex Table 1, Recommendation 5).
While recognising the existence of ethical objections and legal constrains, the report leaves open a
normative evaluation of their proposals. Likewise, the national Academies report proposes clinical
evaluation plans to evaluate human embryos prior to transfer and subsequent long-term
monitoring of outcomes, e.g. monitoring resulting pregnancies and long-term follow-up of
resulting children and adults (Annex Table 1, Recommendation 6). Informed consent and availability
of genetic counselling are mentioned as important, but the different aspects and consequences of
patient agency decisions are not considered. Furthermore, it does not discuss policy options
concerning accessibility and availability of medical services related to the proposed life-long clinical
monitoring. (National Academies, 2020, pp. 135-138).
Finally, a very important recommendation of the National Academies is that an 'International
Scientific Advisory Panel' (ISAP) should be established (Annex Table 1, Recommendation 9). The ISAP
should be composed of independent diverse and multidisciplinary experts and be tasked with
monitoring and assessment of scientific and clinical developments (National Academies, 2020,
pp.158-165). Additional international mechanisms are also recommended for further uses of HHGE
(Annex Table 1, Recommendations 10 and 11).
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Simultaneously, the Expert Advisory Committee developed a 'Governance Framework' (WHO, 2021).
It is a document informed by previous reports on genome editing issues by national ethics
committees (including some of the below analysed in section 5.3) as well as the national academies
report (see above section 5.1).
Unlike the recommendations, the governance framework is not only directed to the WHO
institutional activities but has the broader goal 'to help those tasked with strengthening oversight
measures, regardless of whether this is at the international, regional, national or institutional level'
(WHO, 2021, p.1).
The proposed framework does not put forward differentiated principles concerning different types
of genome editing but focuses simultaneously on all types of genome editing. This is explained
because the Expert Advisory Committee initial mandate covers both somatic, germline and
heritable human genome editing, but also due to interdependencies between these categories - for
example it is referred that somatic interventions may result in heritable changes, even when such is
not the goal of the procedure (WHO, 2021, p.16). The Governance Framework identifies a series of
identified procedural and substantive values and principles to inform both how and what decisions
are made (Annex Table 3). These are divided into:
(1) Ethical values and principles and corresponding commitments to inform how decisions are
made: 'Openness, transparency, honesty and accountability'; 'Responsible regulatory
stewardship'; 'Responsible stewardship of science' and; 'Responsible stewardship of research
resources'.
(2) Ethical values and principles and corresponding commitments, to inform what decisions are
made: 'Inclusiveness', 'Caution', 'Fairness', 'Social justice', 'Non-discrimination', 'Equal moral
worth', 'Respect for persons', 'Solidarity', and 'Global health justice'.
Many of these principles can easily be related to corresponding fundamental principles of
International and EU law and as such are directly or indirectly and to a large extent already part of
the existing legal and regulatory framework applicable in EU Member States (see below section 6).
An important and interesting feature of this proposed framework is that it developed and explored
five specific special challenges: (1) postnatal somatic human genome editing; (2) prenatal (in utero)
somatic human genome editing; (3) heritable human genome editing; (4) human epigenetic editing;
and (5) enhancement (WHO, 2021, part 3). For each, challenge the Governance Framework identifies
and explores a series of questions that should be considered when reviewing or creating oversight
measures (WHO, 2021, part 3).
The Governance Framework also presents a list of possible governances tools (defined as
'Declarations, treaties, conventions, legislation and regulations'; 'Judicial rulings'; 'Ministerial
decrees'; 'Conditions on research funding', 'Moratoria' 'Accreditation, registration or licensing',
'National science and medicine societies and institutions', 'Patents and licences', 'Professional self-
regulation', 'Public advocacy and activism', 'Research ethics guidelines and research ethics review',
'Collaboration with publishers and conference organisers', 'Education and training of researchers
and clinicians'.
There is some overlap in categories, and it is recognised that these are to be used cumulatively or
alternatively depending on the scope and nature of the institutions (WHO, 2021, part 4).
Additionally, the Governance Framework also explores a series of seven mostly hypothetical, but
realistic scenarios used as examples on how to apply the framework (WHO, 2021, part 5). These were
object of specific public consultation/call for opinions.
Overall, the report is very comprehensive, and even if the committee mandate was restricted to
those governance aspects in the sphere of institutional activity of the WHO, it approaches also
important related topics such as intellectual property and patent governance in the health sector
putting clear emphasis in collaboration with other international organisations, such as the World
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research community, citing unknown risks and other methods available to avoid serious inheritable
diseases – preimplantation genetic diagnosis, gametes donation and adoption. The council also
encourages a broad societal debate on these issues (SMER, 2015). In 2018 SMER issued a statement
concerning the birth of genome edited children, announcing a request for a parliamentary
investigation on developing a policy for genome editing and possible legislative changes (SMER,
2018).
The Danish Council on Ethics, critically considers 'the most frequent arguments for and against
genetic modification of future humans' organised in seven 'ethical themes': (1) weighing the risks;
(2) interests of the future child and of the parents; (3) right to an open future (citing Habermas);
(4) genetic modification increases inequalities; (5) natural order; 6) biological diversity 1: tolerance
and solidarity; and (7) biological diversity 2: standardisation and totalitarianism (Danish Council on
Ethics, 2015, pp. 7-11).
Answering the question of whether 'genetic modification of germ cells and fertilised eggs be
allowed with the intention of removing susceptibility to disease in future children and their
offspring?' the Danish Council issued two opinions.
The majority opinion is that it would be ethically irresponsible to offer genetic modification of future
human beings. The main argument is based on safety risks and uncertainty of potential side effects,
complemented by the following: (a) genome editing does not respond to urgent serious therapeutic
need of an existing person; (b) risk of side effects in future generations; (c) interference with human
nature; (d) availability of alternatives – gamete selection or adoption; (e) germline editing narrows
the perception of normality and tolerance towards difference; (f) The difficulty of drawing a line
between disease and normality and slippery-slope effect.
The minority opinion argues that there is no ethical difference between treating a child for a given
disease after or before birth, as such decisions are always a matter of balancing the risks, potential
benefits, and alternatives (Danish Council on Ethics 2015, p. 11-12).
The Italian Committee for Bioethics stresses the importance of an ample public dialogue conducted
on various perspectives: scientific, ethics and social. It recommends that public debate takes into
account both issues relating to efficacy and safety, but also, the ethical implications of the
introduction of genetic modifications potentially transmissible to future generations and the need
to find areas of shared international consensus. In this regard, proposing that research continues to
be conducted in vitro and/or using animal models.
Furthermore, the Italian Committee for Bioethics It considers ethically acceptable and desirable a
strong promotion of research on human somatic cells editing, in accordance with existing research
ethics rules. IT considers ethically unjustifiable experimentation on gametes intended for
conception and human embryos intended for implantation and supports a call for an international
moratorium.
Regarding in vitro research on gametes and embryos not intended for implantation the committee
is divided: some members believe that the moratorium against clinical research should not extend
to basic in vitro research to avoid completely blocking the development of the technology; while a
second group argues that research is currently not justified since it is not possible to verify the results
of genome editing on embryos in vitro in terms of its efficacy and safety, given that these can only
be evaluated after birth (Italian Committee for Bioethics, 2017, pp. 22-23).
The Spanish Bioethics Committee (CBE) issued a declaration in 2019. It starts by stressing that
germline editing generally raises serious conflicts and problems not only scientific but also ethic and
social. It adds that genome editing offers great hope to treat genetic based diseases, but the
techniques are not safe enough for clinical use. The CBE emphasises that decisions to apply genome
editing techniques and corresponding therapies can never be object of sole private initiatives and
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that the use of genome editing with purposes, direct or indirectly, of enhancement (as reported in
the He experiment) is absolutely reproachable and inadmissible. It considers that the United Nations
Educational, Scientific and Cultural Organisation (UNESCO) declarations and the Oviedo Convention
show universal consensus on this matter. Finally, it appeals to the scientific community and society
in general to ensure that the use of these techniques will be subject to respect for the dignity and
equality of all human beings, and to the principles of responsibility, caution and safety (CBE, 2019).
In May 2020, the Nuffield Council on Bioethics, the German Ethics Council and the French National
Advisory Committee on Ethics in Life Sciences and Health (CCNE) made a joint statement on the
ethics of heritable human genome editing (Bioethics Councils, 2020). This joint statement has as
background previously published reports by each of the supra mentioned ethic councils, and
punctuates that, although the three councils made different recommendations, these are to be seen
as complementary and inform on what appropriate ethical principles should be taken into account
and the role they should play (Bioethics Councils, 2020).
Primarily, the Bioethics Councils emphasise that it is of fundamental importance 'that any ethically
permissible application should not increase disadvantage, discrimination or division in society (the
principle of solidarity and social justice)' (Bioethics councils, 2020). The Nuffield Council further
proposes the principle that any intervention should be consistent with the welfare of the future
person, while the French and German councils agree on putting considerable focus on the ethical
concepts of non-maleficence and beneficence. In addition, the German Council highlights the need
to consider the ethical concepts of human dignity, protection of life and integrity, freedom,
naturalness and responsibility (Bioethics councils, 2020).
An important feature of this joint statement and of the prior supporting reports is that all three
councils find that the clinical application of heritable genome editing could be morally permissible
in certain circumstances. It is punctuated that the ethical councils do not 'consider the human
germline categorically inviolable' (Bioethics councils, 2020, p. 3). Namely, there is agreement that
heritable genome editing could be acceptable to prevent the intergenerational transmission of
serious hereditary disorders.
There are, however, national differences in the ethical evaluation of specific applications of genome
editing. The French council maintains a complete opposition to 'enhancement' applications, while
the German council opts by an assessment of such applications on a case-by-case basis, and the
Nuffield Council (UK) does not consider useful a categorical distinction (between therapy and
enhancement) and instead punctuates that assessment must take into account the interests and
responsibilities of those affected in a given sociotechnical context.
In conclusion the topics debates, approaches and opinions of national ethical bodies in Europe,
show commonalities but also a plurality of visions, discourses and arguments, sometimes to the
point that even internally unanimity is not possible and minority opinions or currents of reasoning
are reported. Demonstrating just how complex it is to develop generally accepted European ethical
principles for human genome editing.
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The EGE makes an overview analysis of ethical issues raised by genome editing technologies,
concluding with three common recommendations covering 'overarching matters and concerns',
and a series of specific recommendations on each type of genome editing -human, animal, plant or
gene drive (EGE Opinion 32, 2021 p. 86). This section summarises the main features of the
recommendations applicable to human genome editing:
Common recommendations
(1) Foster broad and inclusive societal deliberation on genome editing in all fields of application
and with a global scope;.
(2) Avoid narrow conceptualisations to frame debates about the ethics and governance of genome
editing.
This recommendation includes a call to 'extend the scope of analysis and debate to underlying
concepts and approaches,' since 'traditional dichotomies and divisions, such as those between
somatic and germline genome editing, between therapy, prevention and enhancement, or
between basic, translational and clinical research can […] constitute artificial, meaningless or
misleading boundaries';
(3) Develop international guidelines and strengthen national, regional and global governance tools.
In this regard, the EGE highlights the need and recommends the establishment of regulatory
oversight for 'do-it-yourself' (DIY) genome editing tools (EGE Opinion 32, 2021, p. 87).
Specific recommendations concerning human genome editing
(1) Engage in global governance initiatives and create a platform for information sharing and
inclusive debate on germline genome editing.
The EGE considers important that the EU participates in global governance mechanisms with a
goal to 'guarantee that heritable human genome editing is not prematurely clinically applied
and is not applied for purposes other than against serious diseases that cannot be prevented or
treated otherwise'. Cumulatively, it also advises the creation of a European Platform on germline
editing for fostering information sharing, public debate and awareness (EGE Opinion 32, 2021,
pp. 86-87).
(2) Establish a public registry for research on germline genome editing
The EGE believes that transparency and evidence-based information are of utmost importance
to foster an inclusive societal debate. To support such debate, it recommends the establishment
of a European and/or global registry for germline genome editing. The registry could be part of
the above-proposed European Platform and should cooperate with the global registry for human
genome editing established by the WHO. The registry should be publicly accessible to ensure
transparency and each entry should be subject to prior ethical approval and compliance with
legal requirements (EGE Opinion 32, 2021, p. 87).
(3) Protect social justice, diversity and equality
The EGE stresses the values of protecting human dignity, identity, diversity, equality, social
justice and solidarity, urging the EU to proactively develop safeguards 'against enhancement or
de-enhancement of traits and to ensure that investments in research on germline genome
editing have the purpose of protecting health' (EGE Opinion 32, 2021 p. 87).
The EGE also considers that the use of categorisation of technologies as a tool for ethical
evaluation requires the development of guidelines capable of allowing research ethics
committees to distinguish between regulatory relevant categories such as 'the definition of
technologies and applications of genome editing to be considered as preventive, diagnostic or
therapeutic, and those that are to be considered as 'human enhancement' (EGE Opinion 32,
2021, p. 87).
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Access to new therapies based on somatic genome editing is also pointed as a concern, and the
EGE urges EU institutions to ensure that such access is guided by the principle of social justice
and without discrimination (EGE Opinion 32, 2021, pp. 87-88).
(4) Ensure adequate competencies in expert bodies
It is considered 'important to widen the basis of expertise and broaden what counts as relevant
knowledge at the level of expert committees' and ensure adequate training. The EGE expresses
concern with and advises action to prevent 'ethics dumping' through international research
collaborations, meaning the delocalisation of research to locations with more permissible
regulations and research ethics standards (EGE Opinion 32, 2021 p. 88).
The EGE opinion on genome editing offers a comprehensive and deep ethical reasoning on genome
editing. In similarity to other reports, the EGE Opinion also advises against using some
categorisations common in ethics literature for regulatory purposes (heritable v non-heritable;
somatic v germline, enhancement v therapy). Particularly where such categories are known to be
extremely difficult to define with precision in scientific, ethical, and legal terms, and/or are also
charged with historical and ethical valuation. However, regardless of this warning, in its
recommendations on concrete actions the EGE recommends mostly actions concerning monitoring
and regulation targeting germline editing and enhancement as a category.
4.5. Conclusion
The current analysis revealed that the ethics and scientific community, represented by a broad range
of disciplines connected with medicine, health care and its regulation either through ethics or
regulation, has been strongly invested in the discussion of genome editing, and that there is a broad
consensus that regulation and governance mechanisms and frameworks are necessary.
The ethical, legal and social implications and relevant aspects of human genome editing are usually
divided in two major blocs, depending on whether the intervention is restricted to the patient or
also affects descendants. Somatic interventions are considered from a perspective of medical and
health law and regulatory approval of medical and pharmaceutical products for human use.
Interventions on the human germline are, on the other hand, considered to pose global and broader
risks to humanity and civilisation.
However, such traditional divide, that has so far also been present in the legislative and regulatory
framework, has recently been bridged in most above-mentioned reports. It has been widely
recognised that scientific advances in genetic knowledge and genome editing technology imply
that each intervention risks and benefits requires a deeper consideration depending on a complex
number of factors, medical, ethical, and social that cannot be simply reduced to whether an
intervention provokes or not hereditary modifications.
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the EU countries, but this convention, although very influential, has not been ratified by all EU
Member States.
The EU has not directly regulated genome editing. However, it has produced several legislative
instruments that are applicable to this technology and contribute to a certain degree of EU internal
legal harmonisation – e.g. Biotechnology Directive, Clinical Trials Directive/Regulation, research
ethics rules, etc.
Despite these efforts, as will be illustrated in this section, considerable divergence exists between
national regulations determining how genome editing tools can be used in clinical practice, as well
as considerable diversity of legal interpretation of the legal framework.
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This legal principle has influenced and is present and developed in subsequent legal texts. It has
also originated vivid debates concerning its interpretation and implementation (Nordberg et al.,
2020). The Human Genome Declaration establishes a principle of non-discrimination (Article 6,
Human Genome Declaration) and respect for human dignity regardless of genetic characteristics
and against any ideology that reduces individuals to such genetic characteristics, linking respect for
human dignity to respect for each individual 'uniqueness and diversity' (Article 2, Human Genome
Declaration). It recognises both that the human genome by nature evolves and is subject to
mutations, and that 'it contains potentialities that are expressed differently according to each
individual's natural and social environment including the individual's state of health, living
conditions, nutrition and education'. (Article 3, Human Genome Declaration). It further addresses
uses of genetic interventions by establishing a principle of prior assessment of potential risks and
benefits of both research, treatment or diagnosis affecting an individual's genome, subject to free
and informed consent; as well as the right of each individual to decide whether or not they wish to
be informed of the results of any genetic examination (Article 5, Human Genome Declaration).
The Human Genome Declaration prohibits practices contrary to human dignity and invites States
and competent international organisations to co-operate in identifying such practices and in taking
appropriate measure against them. It specifically points out reproductive cloning of human beings
as one such practices (Article 11, Human Genome Declaration). It also directs States to 'recognise
the value of promoting, at various levels, as appropriate, the establishment of independent,
multidisciplinary and pluralist ethics committees to assess the ethical, legal and social issues raised
by research on the human genome and its application' (Article 16, Human Genome Declaration).
Although germline editing is not prohibited directly, Article 24 mandates the UNESCO's
International Bioethics Committee (IBC) to provide advice regarding 'practices that could be
contrary to human dignity', identifying human germ-line interventions as a bench-mark example.
This provision clearly signals that germline interventions are considered highly problematic. The
wording choice and the use of the verbal form 'could be contrary', implies that determining whether
a given germline intervention might offend human dignity could depend on the specific context or
at the very least indicates lack of consensus on a total ban. As the IBC later recognised its 2015 Report
on Updating Its Reflection on the Human Genome and Human Rights, the constant and fast
developments in genetics require continuous reflection and re-interpretation of the principles set
in these declarations (IBC, 2015, pp. 127-128).
It is also evident that the Human Genome Declaration is aimed at preventing states from using
genetic knowledge and technologies to implement eugenic experiments, programs or
discriminatory practices. However, the potential for therapeutic uses of the technology sparked a
major point of debate. Eugenic ideologies and practices are a painful and abhorrent historical
memory, but there is real danger that genome editing technology will be used in unethical ways.
However, the declaration cannot be interpreted as prohibiting access to therapeutic interventions
that can cure diseases or prevent pain, suffering and death in families affected by genetic mutations,
since such would collide directly with the right to health and right to benefit from science.
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Declaration). In this sense, declaring the human genome to be a heritage of humanity should not
entail reducing humanity to its biological dimension. The International Declaration on Human
Genetic Data re-affirms a broad construction of the concept of personhood as not merely define by
biology and stating that 'a person's identity should not be reduced to genetic characteristics, since
it involves complex educational, environmental and personal factors and emotional, social, spiritual,
and cultural bonds with others and implies a dimension of freedom' (Article 3, Genetic Data
Declaration).
The principle of non-discrimination and non-stigmatisation is of special interest for human genome
editing, as it prescribes that the international community should ensure that human genetic data
and human proteomic data are not used for purposes that discriminate – e.g. directly or indirectly
'infringing human rights, fundamental freedoms or human dignity of an individual'- or used 'for
purposes that lead to the stigmatisation of an individual, a family, a group or communities' (Article
7(a), Genetic Data Declaration). Indirectly, this principle also entails that genetic data, for example
'population-based genetic studies and behavioural genetic studies and their interpretations' (Article
7(b), Genetic Data Declaration), should not be used to identify future disabilities where such might
result in discrimination (e.g. in employment or insurance) or violation of human dignity (e.g. using
such information to pressure or mandate individuals and families to undergo genome editing
therapy or preventive medicine programs).
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therapeutic alternatives for the individual, and conducted according to medical best practices and
medical law rules and regulations concerning high risk procedures.
The explanatory report to the Oviedo Convention, which has interpretative value (para 90,
Explanatory report Oviedo convention), clarifies that Article 13 'does not rule out interventions for
a somatic purpose which might have unwanted side-effects on the germ cell line', thus making a
legal distinction between aim and result of a given intervention (para 92, Explanatory report
Oviedo convention). It also punctuates that the protection of the dignity and identity of all human
beings is the primary goal and general interpretative guiding principle of the Convention (Article
1, Oviedo Convention). Dignity and identity are here understood as protecting the biological and
genetic identity of the species (Article 2, Oviedo Convention) and inspired by the principle of the
primacy of the human being (para 22, Explanatory Report Oviedo Convention). Arguably, this
principle can be respected even allowing genome-editing interventions where the objective is to
prevent or correct genetic mutations, since these can be seen to be by themselves a threat to the
integrity and future of human identity (para 92, Explanatory Report Oviedo Convention).
Already in 1982, the Council of Europe (CoE) Recommendation 934 on Genetic Engineering
explicitly states that 'the rights to life and to human dignity protected by Articles 2 and 3 of the
European Convention on Human Rights imply the right to inherit a genetic pattern which has not
been artificially changed' (para 4a, CoE Rec. 934), adding that recognition of such right 'must not
impede development of the therapeutic applications of genetic engineering (gene therapy), which
holds great promise for the treatment and eradication of certain diseases which are genetically
transmitted' (para 4c, CoE Rec.934).
The drafters of the Oviedo Convention were aware that technology development could affect the
normative content, and thus debated the possibility for creating exceptions. At the time,
concluding that such was premature and thus consistently stressed the need for Article 13 to be
reviewed after a certain period of time to avoid precluding future genetic therapies (Preparatory
Works Oviedo Convention, p 63-68).
Posterior advances in science and society offer new perspectives to legal interpretation if the
relevance of the literal and historic element is tempered with a contextual dynamic legal
interpretation. Such is supported by a broad and consistent application of the elements of
interpretation of international treaties mentioned in Articles 31 and 32 of the Vienna Convention.
The Committee on Bioethics of the Council of Europe, December 2015 issued a Statement on
genome editing technologies (DH-BIO/INF (2015) 13 Final), pointed out that technologic
developments new advances justify public debate (Article 28, Oviedo Convention) and therefore
agrees to examine issues brought by genome editing. As part of its Strategic Action Plan on Human
Rights and Technologies in Biomedicine (2020-2025), the Committee on Bioethics of the Council
of Europe decided to examine Article 13 of the Oviedo Convention in the light of developments in
genome editing technologies with the objective to evaluate whether there is a need to clarify or
amend Article 13. More recently, at its 18th plenary meeting (1-4 June 2021), the Committee on
Bioethics of the Council of Europe concluded that 'conditions were not met for a modification of
the provisions of Article 13. However, it agreed on the need to provide clarifications, in particular
on the terms 'preventive, diagnostic and therapeutic' and to avoid misinterpretation of the
applicability of this provision to 'research'' (DH-BIO 2021) and announced ongoing work to 'Set up
a drafting group' (www.coe.int).
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concerning genome editing technologies and interventions (de Miguel Beriain, 2017). This being
followed by a second observation that such is not equivalent to a legal vacuum, since general
principles and rules are relevant and applicable to a variety of situations and may also be relevant
for interventions on the human genome. EU Pharmaceutical Law is composed of a long list of
complex legislative instruments (for a full list see EUDRALEX vol 1 to 10) that are applicable also to
human genome editing products.
Mentions to interventions in the human genome can be found in a variety of EU instruments, such
as the Biotechnology Directive (Directive 98/44/EC); the Clinical Trials Directive/Regulation
(Directive 2001/20/EC; to be replaced by the full entry into force of Regulation 536/2014); the
regulations on advanced therapy medicinal products (ATMP) (Regulation (EC) No 1394/2007;
Directive 2001/83/EC; Regulation (EC) No 726/2004); Directive on investigational medicinal products
for human use (Directive 2005/28/EC); to be replaced once the Clinical Trials Regulation entries into
force and replaced by Commission Implementing Regulation (EU) 2017/556); the Human Tissues
and Cells Directive (Directive 2004/23/EC). Furthermore, outside of the scope of this report, but also
relevant, are the data protection rules in the General Data Protection Regulation (Regulation (EU)
2016/679).
The EU legal framework here presented, should be understood within the context of the intersection
of legal sources sometimes with an unclear or disputed hierarchical relationship between them, and
a complex interface between the EU and national member state respective legislative competences.
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Biotechnology Directive
The Biotechnology Directive (Directive 98/44/EC) clarifies and harmonises certain aspects of
patentability of biotechnological inventions. It is intrinsically connected with the European Patent
Convention (EPC), a pan-European international treaty establishing the European Patent
Organisation (38 Member-states) and an organisation - the European Patent Office (EPO) –
responsible for processing, examining and granting grants covering the Contracting States and
States that have concluded extension and validation agreements with the EPO. The Biotechnology
Directive substantive rules have been incorporated in the EPC implementing rules (Decision of the
Administrative Council EPO, OJ EPO 7/1999), ensuring correspondence between European and EU
patentability rules.
Patent rights are important incentives to innovation. As such, patent law norms that exclude,
prohibit, or limit the ability of inventors to obtain, dispose and enforce patent rights assume an
indirect public and private governance function. This governance function is exercised through
public governance tools, including for example legal rules on patentability and patentability
exclusions, exceptions, and enforcement limitations; but also, through private governance
mechanisms, such as licensing agreements, enforcement strategies and technology use policies
(Matthews et al., 2021).
Patent rights are not positive rights, but rather provide an entitlement to market exclusivity,
meaning an exclusive right to prevent others from using a patented product or process, and from
making, offering for sale, selling or importing for these purposes a patented product or a product
obtained directly by a patented process (Article 62 EPC, in conjunction with Article 28 TRIPS).
Patents are granted independently of market regulatory approval (Article 4quater Paris Convention;
Article 27 (2) TRIPS in fine; Article 53 (a) EPC in fine). The grant of a patent cannot be refused, nor a
patent invalidated merely on the ground that the sale of the patented product or of a product
obtained by means of a patented process is subject to legal prohibitions or restrictions. Conversely,
refusal of the patent office to grant a patent does not mean that the technology will not be allowed
into the market.
Regardless of a technology being patented or not, it is up to the different regulatory authorities to
decide, in accordance with existing regulations, whether to allow, restrict or prohibit products or
methods and in some cases some possible uses of a given technology. Regulations determine also
which uses are permitted, whether the technology can be used by and sold directly to the general
public or requires intervention of certified professionals (e.g. prescription medicines), and what
safety measures should be in place.
Patent law contains a number of exceptions to patentability, including the 'ordre public' and
morality provision (Article 53 (a) EPC and Article 6 Biotechnology Directive). Certain exceptions to
patentability function as a public governance mechanism, either by excluding certain inventions
from the patent incentive mechanism discouraging investment in research and development of
inventions whose commercial exploitation is considered unethical, or by signalling that innovation
in certain areas should not be object to private entitlements - e.g. medical method (Article 53(c) EPC)
(see with further references Nordberg, 2017a, pp. 82-92). Exceptions act as governance tools also
through a pedagogic or market-signalling effect (Long, 2002; Carvalho 2010, pp. 30-47), conveying
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that those inventions will not benefit from the market exclusivity conferred by patents, thus
signalling the importance of compliance with the core ethical values of society.
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technology is heavily patented in a complex, ripe with litigation landscape (Matthews et al., 2021,
Nordberg et al., 2018, IPSTUDIES, 2020). Patent rights provide a measure of control on how the
technology is used. Patent holders directly exploiting their patents decide what type of products
will incorporate their patented inventions and what sales channels to use. Right holders can also
decide whether to allow third parties to use a patented technology by issuing a license and
negotiate licencing terms and conditions. There are different types of licences and licensing
strategies.
Exclusive licensing was a common strategy for earlier genome editing patents (Graff & Sherkow,
2020). Patents were at the time owned by a relatively small number of actors who licensed it
exclusively to spin-off companies with an exclusive right to sub-license. This practice known as
surrogate licensing was relatively common in the CRISPR context, where patent holders transferred
to surrogate licensing companies' exclusive rights to use patented CRISPR technologies to develop
any human therapeutics, targeting any gene on the human genome (Contreras & Sherkow, 2017).
Collaborative licensing refers to licensing agreements negotiated simultaneously by multiple patent
holders to license clustered patented technologies through one third party license for a reasonable
royalty. In areas where patent ownership is fragmented, collaborative licensing mechanisms are
considered useful mechanisms and recently, initiatives have emerged to explore their potential.
There are two main types of collaborative licensing strategies - patent pools and clearing houses
(Van Zimmeren, 2011; Minssen, Van Zimmeren & Wested, 2018). In April 2017, MPEG LA (self-
described as the world's leading provider of one-stop licenses for standards and other technology
platforms) issued an invitation to patent holders to participate in a CRISPR-Cas9 patent pool
(O'Reilly/ MPEG LA, 2017). In response, prominent actors in the CRISPR-Cas9 patent landscape - the
Broad Institute, the Rockefeller Institute, Harvard University and Massachusetts Institute of
Technology - announced the intention to join (GEN, 2017).
However, ongoing litigation between the participants and exclusive licenses granted cast a shadow
over the feasibility of such endeavour (Contreras & Sherkow, 2017). MPEG LA has announced the
possibility to exclude in the pool licensing conditions authorisation to certain uses of the
technology. In theory, such ethical licencing provisions and private initiatives could play a relevant
role in human genome editing governance (Guerrini et al., 2017; Sherkow, 2017). However,
commentators have highlighted democratic deficits and limitations of such model (McMahon, 2020;
Feeney et al., 2021).
In general, patent licensing practices play a significate technology governance role and can have
long tail effects, positive and negative, on further research and access to health technology.
Licensing and enforcement strategies and practices are already used by relevant actors (companies,
universities, research facilities) not only to ensure technology control, but also to foster socially
responsible use (Matthews et al., 2021).
Patent licensing operates under the general principle of contractual freedom, where parties are free
to decide and negotiate terms. Due to a general absence of legal constraints on licensing practices
(besides competition rules), there is in practice a transfer of regulatory power from public (law) to
private actors (contracts) at the cost of transparency, accountability and legal certainty. This is
certainly an area were further development of governance tools, including regulation, would be
beneficial.
Clinical trials and market approval of medicinal products for human use
The testing and market introduction approval of any therapeutic uses of genome editing tools is
subject to EU harmonised rules under the Clinical Trials Directive (Directive 2001/20/EC), replaced
from 31 January 2022 by the Clinical Trials Regulation (Regulation 536/2014); the regulations on
advanced therapy medicinal products (ATMP); and the extensive and complex legal framework
governing medicinal products for human use. Clinical Trials are also subject to the governance
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principles created by the Declaration of Helsinki on Ethical Principles for Medical Research Involving
Human Subjects, adopted by the General Assembly of the World Medical Association (Helsinki
Declaration 1996) and ICH guidelines on good clinical practice (Article 47, Regulation 536/2014).
The requirements and procedures for marketing authorisation, as well as the rules for monitoring
authorised products, are primarily laid down in the Community Code Relating to Medicinal Products
for Human Use (Directive 2001/83/EC) and in Regulation (EC) No 726/2004 establishing the
European Medicines Agency (EMA).
Other relevant legislation includes Directive 2005/28/EC containing inter alia detailed guidelines for
good clinical practice and the requirements for authorisation of the manufacturing or importation
of gene therapy products and techniques (Article 10 2005/28/EC). This directive is soon to be
repealed once the CTR entries into force, but similar rules will remain applicable. Finally, if /when
human tissues and cells are used as starting materials for genome editing products, rules concerning
the donation, procurement and testing of such tissues and cells are regulated by the Human Tissues
and Cells Directive (Directive 2004/23/EC).
Genome editing uses in, for example, human reproductive technology (ART) or advanced therapy
medicinal products (ATMPs), including also techniques used in the process, have to be tested in
clinical trials to meet the requirements for market authorisation. Article 9(6) of the Clinical Trials
Directive (see also articles 4 to 14 in the CTR) prescribes that 'No gene therapy trials may be carried
out which result in modifications to the subject's germline genetic identity.' This sentence has also
been incorporated in Article 90 of the new EU Regulation on Clinical Trials, which is meant to replace
it once it entries into force. This restriction on conducting clinical trials results in an unsurpassable
hurdle, making it in practice inviable to obtain market approval for related medical products and
therapies, and thus an impediment to commercialisation as a human medicinal product.
The use of the open concept 'genetic identity', also present in the international framework is difficult
to implement in practice. Indeed, there is very little guidance to determine what can be concretely
considered as the germline genetic identity of a given person participating in a human clinical trial
as a subject, for example whether it also includes mutations. It also to be determined whether
germline genetic identity should be constructed as an autonomous concept of EU Law or is a matter
of pure factual determination.
The ATMP Regulation 'lays down specific rules concerning the authorisation, supervision and
pharmacovigilance of advanced therapy medicinal products' (Article 1, Regulation 1394/2007
ATMP). It is thus mostly concerned with the evaluation of quality, safety and efficiency of advanced
therapy medicinal products. The ATMP Regulation is lex specialis to Directive on the Community
Code relating to Medicinal Products for Human Use (Dir. 2001/83/EC Medicinal Products Code)
meaning that it introduces additional and more specific provisions. Neither legislative instrument
regulates specifically what possible uses of genome editing products are allowed.
The Medicinal Products Code contains definitions of gene therapy medicinal product and somatic
cell therapy medicinal product, which require that these products are used for treating, preventing
or diagnosing a disease (2.1. and 2.2., Part IV, Annex I Directive 2001/83/EC). This implies that the
rules prescribed in the Code are only applicable to gene therapy products that have such purposes.
Products that cannot be justified as therapeutic (e.g. products with cosmetic or wellness purposes)
are outside the scope of this regulatory framework. Another concern is that the current definition of
gene therapy medicinal products 'risks excluding molecules which are not manufactured through
techniques involving recombination' (Mourby & Morrison, 2020).
The Clinical Trials Directive/Regulation and the specific rules mentioned above concerning ATMPs
are only applicable to specific medicinal products, and within the limited context of clinical trials
and market authorisation procedures, for example concerning clinical trials involving medicinal
products for gene therapy, somatic cell therapy including xenogenic cell therapy and all medicinal
products containing genetically-modified organisms. While having a governance effect through
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influencing the research community and industry, these regulations do not directly regulate clinical
uses of genome editing, nor any uses outside a healthcare setting.
This regulatory framework contains three mechanisms created to ensure that patients in need of
urgent care do not have to wait for the long process of marketing approval and that early access can
be allowed in specific well justified circumstances. These are: compassionate use, named-patient
use, and specific to ATMP's the hospital exception.
Compassionate use was created by Article 83 of Regulation (EC) No 726/2004. The EMA, through the
Committee for Medicinal Products for Human Use (CHMP), provides recommendations on how a
product should be used and what type of patients may benefit from treatment, but compassionate
use programmes rules and procedures are determined and implemented by each Member State.
Named-patient basis are access requests made under the direct responsibility of an attending
physician and made on an individual patient basis to obtain medicines directly from manufacturers
before market authorisation has been granted.
The hospital exception is specific to ATMP's and is applicable to any ATMP 'which is prepared on a
non-routine basis according to specific quality standards, and used within the same Member State
in a hospital under the exclusive professional responsibility of a medical practitioner, in order to
comply with an individual medical prescription for a custom-made product for an individual patient'
(Article 3(7) Directive 2001/83, Article 28, ATMP Regulation (EC) 1394/2007). It is up to the competent
national authorities to authorise the manufacture of these products. Member states should also
ensure that national traceability and pharmacovigilance requirements, as well as the specific quality
standards are equivalent to those provided for at EU level. As a result, this mechanism is used and
regulated differently in the various member states and the UK (Coppens et al., 2020; see also for a
pharmaceutical industry perspective: Hill et al., 2020).
Finally, genome editing techniques uses and dual uses can raise diverse ethic issues that fall mostly
under the responsibility of individual EU Member States. Hence, local ethics committees are
required to provide an opinion before a clinical trial regarding whether genome editing can be
authorised (Isasi, Kleiderman & Knoppers, 2016). Considering the diversity of ethical positions in
society and their distribution among EU Member States reported above in section 5.3, it can be
expected that the controversies surrounding treatments involving the in vivo use of genome editing
treatments in clinical trials and patients will remain highly complex (idem), and difficult to further
harmonize without specific legislation.
Research funding
Technology governance can be exercised indirectly through specific rules for access to research
funding offered by agencies and programs, both at Member State and EU level. These rules can
exclude technologies from funding and create demands of ethical approval and other compliance
mechanisms.
The EU and Member States share competencies in the area of research and technological
development (Article 4, Treaty on the Functioning of the European Union). The Treaty on the
Functioning of the European Union (TFEU) establishes that the Union 'shall have the objective of
strengthening its scientific and technological bases by achieving a European research area in which
researchers, scientific knowledge and technology circulate freely, and encouraging it to become
more competitive, including in its industry' (Article 179, TFEU) and lay down a number of activities
to pursue towards these objectives, including establishing a multiannual framework program for
research and innovation (Articles 179 to 190, TFEU) – currently the research funding program
Horizon Europe (Regulation (EU)2021/695 Horizon Europe).
The Horizon Europe Regulation specifically excludes from EU funding research 'activities intended
to modify the genetic heritage of human beings which could make such modifications heritable' the
only exception being research relating to cancer treatment of the gonads, which can be financed
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(Article 18 (1) (b), Regulation (EU)2021/695 Horizon Europe). The structure of the text suggests that
the rule is broader than a mere prohibition of germline editing but rather aimed also at any research
that could allow to make heritable modifications to the genome, regardless of the type of
techniques employed and even if such modifications are unintended. This is extended also to
activities carried out outside the EU, since a confirmation is required that the research activities
funded would have been allowed in a Member State (Article 19(2)(c), Regulation (EU)2021/695
Horizon Europe).
Compliance with ethical principles and relevant EU national and international law, including the
Charter and the European Convention for the Protection of Human Rights and Fundamental
Freedoms and its Supplementary Protocols is required (Article 19 (1), Regulation (EU)2021/695
Horizon Europe). The Regulation also imposes an ethics self-assessment identifying and detailing all
the foreseeable ethics issues and proposals for funding are to be 'systematically screened to identify
actions which raise complex or serious ethics issues and submit them to an ethics assessment'
(Article 19(2)(a) and (3), Regulation (EU)2021/695 Horizon Europe).
ii. France
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Bioethics legislation in France is codified under the Public Health Code, which includes norms
concerning research on embryos and assisted reproduction (Article L2151-2, Public Health Code).
French bioethics legislation is to be updated in light of new technological or scientific
developments, and following a national public consultation held at least every five years. The most
recent public consultation took place in 2018.
The Public Health Code prohibits the creation of research embryos, but it does not provide a
definition of embryo (Article L2151-2, Public Health Code). Research on supernumerary embryos
and human embryonic stem cells is not expressly prohibited and thus is understood as allowed
pursuant to necessary authorisation by the National Biomedicine Agency, a public body created and
regulated by the Public Health Code (Article L2151-5, Public Health Code) (Blassimme et al., 2020).
Conducting heritable genetic modifications in research aiming at preventing or treating a genetic
disease are allowed (Article 16-4, a contrario, Civil Code). Clinical applications of genome editing for
ART purposes or any activity that could damage the integrity of the human species are strictly
prohibited (Article 16-4, Civil Code), and it is also prohibited to transfer to a uterus, with the goal of
starting a pregnancy, embryos on which research was carried on (Article L2151-5, Public Health
Code). Furthermore, genome editing may also be subsumed to criminal laws against eugenic
practices (Articles 214-1, 214-3, 214-4 Penal Code).
iii. Portugal
Portuguese law does not have a specific provision on germline or heritable genome modification,
and the law does not refer to genome editing technology. However, the Act on medically assisted
reproduction (Act 32/2006 of 26 July 2006) limits considerably both clinical uses and research
performed on human embryos. Arguably, the use of genome editing techniques with a clear
therapeutic purpose in ART could be authorised by the ethical research council. However, the use
of ART to improve any non-medical characteristics of the unborn child is punishable severely with
up to 2 years of imprisonment or 240 days fine (Article 37, Act on medically assisted reproduction).
Likewise, reproductive cloning (Article 36, Act on medically assisted reproduction), and the creation
of chimeras and hybrids, results in a prison sentence between 1 to 5 years (Article 38, Act on
medically assisted reproduction).
iv. Spain
Two main acts are relevant to genome editing the 2006 Act on Assisted Reproduction Techniques
and the 2007 Act on Biomedical Research. Spanish Law prohibits expressively the creation of
embryos for experimental purposes (Article 33, Act on Biomedical Research), pursuant to the
doctrine of 'gradualist approach towards human life' adopted by the constitutional court (see
rulings n. 53/1985, 212/1996 and 116/1999). However, it is permissible the use of any techniques of
obtention of embryonic stem cells with both therapeutic goals and research goals as long as it does
not include the creation of an embryo (part III - preamble, Act on Biomedical Research).
Research interventions on supernumerary embryos are permitted with less restrictions (Article 34,
Act on Biomedical Research and Article 15, Act on Assisted Reproduction Technique). Spanish law
permits gamete research, however gametes used in research cannot be transfer into a human
uterus, nor used to develop embryos with the goal to establish a pregnancy (Article 14 (2), Act on
Assisted Reproduction Techniques).
Therapeutic pre-implantation interventions are allowed provided that the goal is to treat a disease
or prevent its transmission. Interventions are subject to requirements of informed consent of the
prospective parent(s), and that there the pathologies of the embryo have a clear diagnostic with
severe or very sever prognosis and that the treatment offers reasonable possibilities of
improvement or cure; that non pathologic hereditary characteristics are modified nor there is goal
of racial selection (Article 13, Act on Assisted Reproduction Technique). Interventions on embryos
and foetus in the uterus, can only be performed with a diagnostic or therapeutic goal and in the
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interest of the embryo/foetus (Article 30, Act on Biomedical Research). Carrying out any intervention
aimed at the introduction of a modification in the genome of the descendant is considered to be a
serious infraction and as such punishable with a fine of between 10.001 and 1.000.000 euros (Articles
74 (2)(c)(a) and 75(1), Act on Biomedical Research).
Some authors argue that Spanish Law allows germline modification as long as the intervention does
not involve the introduction of new genetic material into the human genome, nor have as goal to
change the human genome (even if causing it) (de Miguel Beriain & Casabona, 2020).
EU Member States that have signed but not yet ratified the Oviedo
Convention
i. Italy
The current legislation - The 2004 Act on Medically Assisted Reproduction - is subject to heated
debate and criticism. On different occasions, between 2008 and 2019, some provisions were
declared unconstitutional by the Italian Constitutional Court. Italy has also been condemned by the
European Court of Human Rights in Case Costa & Pavan v. Italy (Application no. 54270/10)
concerning access to pre-implantation diagnosis (Fineschi et al., 2005; Penase, 2012; Molinelli et al.,
2012, Biodirrito Dossier 2017). A legislative proposal for legislative reform has been presented
(Proposal DDL 1630/2014).
The controversial 2004 Act on Medically Assisted Reproduction bans any form of eugenic selection
of embryos and gametes, or interventions which, by means of selection, manipulation or artificial
manipulation, are intended to alter the genetic heritage of the embryo or the gametes or to
predetermine their genetic characteristics, with the exception of the interventions for diagnostic
and therapeutic purposes (Article 13(3)(b), Act N.40/2004).
The Constitutional Court declared in 2015 this provision partly unconstitutional insofar as it
encompasses a prohibition of embryo selection in order to avoid implantation of embryos carrying
severe genetic transmissible diseases (Italian Constitutional Court, decision of 18/11/2015).
The interventions on the embryo currently allowed are very narrowly determined. Clinical and
experimental research on any human embryo is allowed, but only under two cumulative conditions,
that it pursues exclusively therapeutic and diagnostic purposes related to the embryo, aimed at the
protection of the health and development of the embryo itself; and provided that alternative
methods are not available. (Article 13 (2), Act N.40/2004).
These prohibitions are enforced with penalties between 2 to 6 years of imprisonment and fines
between 50.000 to 150.000 euro, and the accessory penalty of suspension from exercising a medical
profession between 1 to 3 years (Article 13(4) and (5), Act N.40/2004; See also European Court of
Human Rights in Case Costa & Pavan v. Italy).
ii. Sweden
Sweden's Act on Genetic Integrity (Act on Genetic Integrity SFS n. 2006:351), prohibits the use of
treatment methods intended to achieve genetic modifications which can be inherited, and
expressively forbids clinical trials with either a research or treatment purpose that involve human
genetic modifications capable of being inherited (Ch 2, Paras 3 and 4, Act on Genetic Integrity). Pre-
implantation diagnostic is only allowed when parents carry a severe monogenic or chromogenic
hereditary disease which has a high risk of resulting in a child with a genetic disease or health
damage.
The Act on Genetic Integrity, further expressively forbids embryo selection to choose specific traits,
limiting selection to situations where the goal is to avoid implantation of embryos that would result
in a child that may inherit a genetic disease or health damage (Ch 4, para 2, Act on Genetic Integrity).
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The recently enacted Act on Aesthetic Surgical Interventions and Aesthetic Injections (Act 2021:363)
could arguably become applicable to somatic genome interventions with a cosmetic purpose.
These are defined as interventions with the purpose to modify or preserve appearance of a person
(para 2, Act 2021:363) and do not specify composition or mechanism of action beyond being
administered by surgery or an injection. The act determines that only licenced medical doctors,
nurses and dentists can perform such interventions (para 8, Act n. 2021:363) and prohibits such
interventions on minors (para 9, Act SFS n. 2021:363).
ii. Germany
Germany objected to the Oviedo convention, as it considered its provisions overly permissible
clashing with its pre-existing legislation. The Embryo Protection Act (ESchG) defines embryo (paras
8.1 and 8.2, ESchG,) and germline cells (para 8.3, ESchG) although it is disputed whether the
definition encompasses artificially created gametes (Faltus, 2020).
The law prohibits basic research on modified gametes adding that these cannot be used for
fertilisation (para 5.4, ESchG); the creation of research embryos (para 1.1, ESchG), and any 'use' of
embryos for any purpose other than their 'preservation', conversely prohibiting embryo destruction
(para 1.1, ESchG; Faltus, 2020).
In theory, genome editing research is allowed as long as it does not result in the destruction of the
embryo. However, due to the legal prohibition on modifying human germline cells and, because
both clinical research and applications are prohibited, the implant of these embryos is punishable
(para 5, ESchG; Faltus, 2020).
The Embryo Protection Act contains criminal enforcement provisions, these have also an extra
territorial scope of application – allowing to sanction of German-based scientists even when the
actions take place abroad, e.g. as part of a research collaboration (para 9(2) Penal Code; Faltus, 2020).
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potentially preventing miscarriages and aiding fertility. The embryos used were not older than
seven days and not intended to be implanted (The Francis Crick Institute, 2016).
The UK was also the first country in the world to allow and regulate mitochondrial replacement
therapy, also known as mitochondrial donation (Human Fertilisation and Embryology Act, 2008).
The procedure is allowed under UK law but only to avoid severe genetic conditions (Section 35A,
c22, Human Fertilisation and Embryology Act). It enables the correction of genetic mutations before
these are transmitted from mother to child through transplant of donor genetic material, by
replacing the mothers' unhealthy mitochondria with a donor's healthy mitochondria, resulting in a
healthy genetic related child inheriting 99.9% of the parents DNA.
In strict legal terms, the technology entails a modification in germ cells transmittable to future
generations, by inserting healthy donor genetic material. However, the UK parliamentary and public
debates carefully avoided the use of the terminology genome editing, manipulation, modification
or similar. Discussions focused mostly on weighting the potential medical risks of using a new
assisted reproduction technique against potential benefits of avoiding pain, suffering and loss of life
associated with severe diseases.
Arguments used to allow and regulate this procedure are interesting to debates on genome editing
since the reasons for allowing mitochondrial replacement therapy can equally apply to therapeutic
uses of genome editing technology (Progress Educational Trust, 2015; Cohen et al., 2020).
5.5. Conclusion
The current legal framework governing human genome editing is complex, fragmented and diverse.
Some general principles, or at least their interpretation, require revision in light of recent scientific
advances. Namely the reliance on categories such as human germline identity or hereditary
modifications to the human genome, is problematic and difficult to interpret. The prohibition of
eugenics and distinctions between therapeutic and other goals also require additional clarification
and specific regulation is often lacking.
Although EU pharmaceutical legislation is comprehensive, experts argue that there is a risk that
some genome editing therapeutic products can never be tested in a clinical trial and that non-
therapeutic somatic editing uses are left unregulated, which may become problematic in the future.
National legislation of EU member states and the UK shows considerable variety, a situation that is
confirmed by recent comparative studies with a broader geographical scope including also non-EU
countries (see Slokenberga et al., 2019; Boggio et al. (Eds.), 2020; Baylis et al., 2020).
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since it is likely that genome editing services and products, real or falsified, will sooner or later also
be advertised and sold through unscrupulous digital channels.
Private governance through technology-licensing agreements and other contractual means (e.g.
terms and conditions of use, company by-laws, voluntary codes of conduct, etc.) already plays a
large role in the governance of emerging technologies. While ethical license pledges are a positive
sign from the industry, there is very little agreement in their normative content (similarity, there is
also considerable discussion on what constitutes a FRAND licence - fair, reasonable, and non-
discriminatory in the context of standard essential patents). Development of general guidance or
model clauses for standard ethical licensing in genome editing and other biomedical innovation
could provide a clear signal to stakeholders and promote good private governance, while
preserving contractual freedom.
Genetic testing, and the use of genetic big data analytics and AI systems both in health care and
other commercial settings is experiencing continuous development. The possibility to use of big
data-based AI systems to identify favourable traits or perceived favourable traits, matching with a
possible non-therapeutic genome editing intervention may because a future area of concern.
Regardless of the type of approach to regulation chosen this is a related area that also would benefit
from a coordinated regulatory intervention.
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8. Conclusions
The present report provides a critical contextual legal analysis and comparison of different
legislative and regulatory approaches to human genome editing, as well as options for general
governance principles and frameworks.
The reviewed literature contains a rich variety of academic discussions, perspectives and opinions
on the ethical, legal and social implications of genome editing. These concentrated on human
germline or hereditary genome editing. A large amount of attention was dedicated to discussing
how and to what degree to enact and enforce prohibitions of eugenics, in particular in the contexts
of assisted reproductive technologies and human enhancement.
Opinions vary from libertarian and techno-optimistic views on human genome editing as a vector
for promoting the wellbeing and moral and physical improvement of humanity, to bio-conservative,
human-nature-inviolability ontological considerations and precautionary approaches to this
technology. Between these extremes on the opinion spectrum, a broad range of opinions and
concerns are directed by specific needs and challenges.
It is widely agreed that the regulation of emerging technologies requires an inclusive, multi-
disciplinary and transversal debate. In this sense, the present report reviewed proposed frameworks
and recommendations for governance and ethical guidance reports. These were issued by different
international bodies and organisations, national ethics councils and the European Group of Ethics.
This analysis revealed a large consensus on the idea that further regulation and governance
mechanisms and frameworks are necessary. Secondly, the ethics and scientific communities,
represented by a broad range of disciplines, are determined to participate in the development of
such discussions. The analysis of ethical, legal and social implications of human genome editing has
until recently been organised in two major groups, depending on whether the intervention is
restricted to a patient/user or also affects their descendants.
Somatic human genome interventions are approached mostly from a perspective of medical and
health law and the regulatory approval of medical and pharmaceutical products for human use,
while interventions on the human germline are considered from ontological viewpoints, as these
are considered to pose global and broader risks to human nature, human civilisation and societies.
This traditional divide was recently bridged in most review reports and statements. It is now
generally recognised that the risks and benefits of each intervention require a deeper consideration,
depending on a complex number of factors (e.g. medical, ethical, and social) that cannot simply be
reduced to whether an intervention involves hereditary modifications or not.
The overview analysis of the existing international, European and EU frameworks and legislation
applicable to human genome editing revealed an extensive but fragmented regulatory framework.
A legal comparison of rule and normative approaches to genome editing in selected EU Member
States and the United Kingdom demonstrates that, while a strong legal and regulatory framework
applicable to genome editing already exists, there are ample opportunities for further development
in certain areas of EU harmonisation, through legislative initiatives, policy guidance or incentives to
private governance.
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Policy options
Inclusive debate(s)
Governance of genome editing should provide forums for inclusive, fair and transversal social debate(s)
with multi-level stakeholders. In particular, opportunities for meaningful participation should be afforded
to individuals and groups representing those more likely to be impacted by technology and its regulation
– researchers, healthcare professionals, patients and their families.
Principles
of Public health and individual safety
governance Inter-, cross- and trans-disciplinary perspectives and approaches should be integrated in the evaluation of
safety concerns and pathways for clinical translation. Including ethical and social science considerations.
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Transnational cooperation
International and EU Member State cooperation and coordination of regulatory efforts and related
enforcement should remain a priority.
European Union
– Harmonisation of legislation at EU level.
– Mechanisms of coordination and oversight via EU institutions (European Medicines Agency – EMEA).
– Revision of the Biotechnology Directive or updated guidelines for interpretation and patent examination;
– Revision of regulations to remove barriers to research and clinical trials for all therapeutic applications
pursuant to careful benefit-risk assessment.
of regulation – Updating national legislation to face the challenges posed by genome editing.
and action – Ensuring the existence of national mechanisms for uncovering breaches of regulations or absence of
regulations and study concerns with the national regulatory authority.
EU international role
– Assuming a leadership role in promoting and developing regulatory efforts and mechanisms.
– EU participation in and support for international initiatives concerning the creation of an international
scientific advisory panel of multidisciplinary, independent experts to assess scientific efficiency and safety.
– EU participation in and support for an international body to make recommendations on accepted uses
and limitations.
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Annex
Table 1 – Recommendations made by the National Academy of Medicine, National Academy of Sciences,
and the Royal Society (adapted from Box S-1, National Academies, 2020)
Recommendation 1: No attempt to establish a pregnancy with a human embryo that has undergone genome
editing should proceed unless and until it has been clearly established that it is possible to efficiently and reliably
make precise genomic changes without undesired changes.
Recommendation 2: Extensive societal dialogue should be undertaken before a country makes a decision on
whether to permit clinical use of heritable human genome editing (HHGE).
Recommendation 3: Clinical use of HHGE should proceed incrementally. It is not possible to define a responsible
translational pathway applicable across all possible uses.
Recommendation 4: Initial uses of HHGE, should be limited to circumstances that cumulatively meet the
following criteria:
Recommendation 5: Preclinical evidence based on a significant cohort of edited human embryos, should a priori
demonstrate that the process has the ability to generate and select, with high accuracy, suitable numbers of
embryos that:
Recommendation 6: A proposal for clinical use should also include plans to evaluate human embryos prior to
transfer using:
• developmental milestones until the blastocyst stage comparable with standard in vitro fertilisation
practices, and
• a biopsy at the blastocyst stage that demonstrates:
− the existence of the intended edit in all biopsied cells and no evidence of unintended edits at the target locus,
and
− no evidence of additional variants introduced by the editing process at off-target sites.
It is vital to monitor a resulting pregnancy and long-term follow-up of resulting children and adults.
Recommendation 7: Research should continue also into the development of methods to produce functional
human gametes from cultured stem cells.
Recommendation 8: Countries considering clinical HHGE should have mechanisms and competent regulatory
bodies to ensure the following cumulative conditions:
− individuals conducting HHGE-related activities, and their oversight bodies, adhere to established principles of
human rights, bioethics, and global governance;
− the clinical pathway for HHGE incorporates best practices from related technologies such as mitochondrial
replacement techniques, preimplantation genetic testing, and somatic genome editing;
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− decision making is informed by findings from independent international assessments of progress in scientific
research and the safety and efficacy of HHGE, which indicate that the technologies are advanced to a point that
they could be considered for clinical use;
− prospective review of the science and ethics of any application to use HHGE is diligently performed by an
appropriate body or process, with decisions made on a case-by-case basis;
− notice of proposed applications of HHGE being considered is provided by an appropriate body;
− details of approved applications are made publicly accessible, while protecting individual privacy (including
genetic condition, procedures, performing laboratory or clinic, and oversight authority);
− publishing in peer-reviewed journals of detailed procedures and outcomes;
− enforcement of norms of responsible scientific conduct;
− researchers and clinicians organise and participate in open international discussions on the coordination and
sharing of results of relevant scientific, clinical, ethical, and societal developments impacting the assessment
of HHGE's safety, efficacy, long-term monitoring, and societal acceptability;
− prior development of practice guidelines, standards, and policies for clinical uses of HHGE,
− deviation from established guidelines is reported, received and reviewed, and sanctions are imposed where
appropriate.
Recommendation 9: An International Scientific Advisory Panel (ISAP) should be established. The ISAP should
have a diverse, multidisciplinary membership and should include independent experts who can assess scientific
evidence of safety and efficacy of both genome editing and associated assisted reproductive technologies. The
ISAP should:
− provide regular updates on advances in, and the evaluation of, the technologies that HHGE would depend on
and recommend further research developments that would be required to reach technical or translational
milestones;
− assess whether preclinical requirements have been met for any circumstances in which HHGE may be
considered for clinical use;
− review data on clinical outcomes from any regulated uses of HHGE and advise on the scientific and clinical risks
and potential benefits of possible further applications;
− provide input and advice on any responsible translational pathway to the international body described in
Recommendation 10, as well as at the request of national regulators.
Recommendation 10: In order to proceed with applications of HHG that go beyond the translational pathway
defined for initial classes of use, an international body with appropriate standing and diverse expertise and
experience should evaluate and make recommendations concerning any proposed new class of use. This
international body should:
− clearly define each proposed new class of use and its limitations;
− enable and convene ongoing transparent discussions on societal issues surrounding the new class of use;
− make recommendations concerning whether it could be appropriate to cross the threshold of permitting the
new class of use;
− provide a responsible translational pathway for the new class of use.
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Table 2 – Recommendations of the WHO Expert Advisory Committee on Developing Global Standards for
Governance and Oversight of Human Genome Editing (adapted from WHO, 2021)
6. Intellectual property
The WHO should:
(i) work with others to encourage relevant patent holders to ensure equitable access to HGE interventions;
(ii) encourage industry to work with resource constrained countries to build capacity to take advantage of HGE
inventions, and
(iii) convene a meeting of those holding or applying for patents relevant to HGE, industry bodies, international
organisations, such as the WIPO and the WTO, and those involved in establishing or running relevant patent
pools to explore the potential for the adoption of appropriate ethical licensing requirements.
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(ii) call for an inclusive dialogue on the future of HGE, including scientific, ethical and societal aspects.
The WHO should:
(i) develop models of best practice of inclusive multidirectional, multistakeholder dialogue, and supporting
materials, that can be applied to HGE, and
(ii) explore how best to include in decision-making under-represented groups.
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STOA | Panel for the Future of Science and Technology
A commitment to:
(i) pursue rigorous, evidence-informed basic and applied research with appropriate caution
for uncertainty and risk;
(ii) follow established ethical practices for research involving humans with particular
Responsible attention to issues of integrity and conflict of interest;
stewardship of science (iii) maximise the potential benefits while minimising the potential harms, and
(iv) respect research ethics guidelines and applicable legislation.
More particularly, a commitment to align the processes and outcomes of HGE with the
values, needs and expectations of society, as identified through participatory approaches
involving various publics.
Responsible A commitment to use responsibly finite research resources (biological materials; research
stewardship of skills, and research funding). This requires careful attention to scientific value and validity,
research resources as well as social value and validity.
Caution A commitment to exercise appropriate caution given existing uncertainty and risk.
Non-discrimination A commitment to celebrate and promote diversity by rejecting concepts of eugenics and
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Genome editing in humans
A commitment to recognise and treat all people as having equal moral worth and their
Equal moral worth interests as deserving of equal moral consideration, with a particular need to recognise and
protect the interests of persons with disabilities and of future generations.
A commitment to respect the wishes of competent individuals regarding the most intimate
aspects of their lives, including their health and their reproductive options. In addition, a
Respect for persons
commitment to promote the best interests of individuals who are not competent to make
decisions for themselves.
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QA-07-22-327-EN-N
Genome editing is a powerful new tool allowing precise
additions, deletions and substitutions in the genome.
The development of new approaches has made editing
of the genome much more precise, efficient, flexible,
and less expensive, relative to previous strategies.
As with other medical advances, each such application
comes with its own set of benefits, risks, ethical issues
and societal implications, which may require new
regulatory frameworks. Important questions raised with
respect to genome editing include how to balance
potential benefits against the risk of unintended harms;
how to govern the use of these technologies, and how
to incorporate societal values into salient clinical and
policy considerations.
This STOA study provides an overview of human
genome editing applications and a review of the
principles that guide the governance of genome editing
in humans, at EU level and worldwide. The study also
formulates a series of policy options targeted at basic
research and to clinical applications, both somatic and
germline.