Hnge Public Consultation Paper - VF

ETHICAL, LEGAL, AND SOCIAL
ISSUES ARISING FROM HUMAN

NUCLEAR GENOME EDITING
A CONSULTATION PAPER
BIOETHICS ADVISORY COMMITTEE
SINGAPORE
JUNE 2024
1
HUMAN NUCLEAR GENOME EDITING (HNGE) REVIEW GROUP
CHAIR
Emeritus Professor Lee Eng Hin
Emeritus Professor, Department of Orthopaedic Surgery,
National University of Singapore (NUS); and
Emeritus Consultant, Division of Paediatrics Orthopaedics,
National University Hospital (NUH)
CO-CHAIR
Dr Chew Wei Leong
Associate Director (Genome Design) and Senior Research Scientist, Genome Institute of
Singapore; and
Adjunct Assistant Professor, NUS
MEMBERS
Emeritus Professor Roy Joseph

Emeritus Consultant, Department of Neonatology,
Khoo Teck Puat - National University Children’s Medical Institute, NUH; and
Director of the Paediatric Ethics Program, Centre for Biomedical Ethics,
Yong Loo Lin School of Medicine, NUS
Associate Professor Lai Poh San

Associate Professor, Department of Paediatrics; and
Deputy Chairman,
Institutional Biosafety Committee, NUS
Associate Professor Lim Tit Meng

Chief Executive,
Science Centre Board
Professor Vineeta Sinha

Department of Sociology,
Faculty of Arts and Social Sciences, NUS
Mr Tan Sze Yao

Director, Legal Office,
Ministry of Health (MOH), Singapore
Ms Joyce Teo
Senior Health Correspondent,
The Straits Times
2
Mr Gregory Vijayendran
Equity Partner,
Rajah & Tann Singapore LLP
Dr Voo Teck Chuan

Head, Office of Ethics in Healthcare,
SingHealth
Professor Tan Sor Hoon (until June 2023)

Professor of Philosophy and Academic Director,
School of Social Sciences,
Singapore Management University (SMU)
Ms Audrey Chiang
Senior Partner,
Dentons Rodyk & Davidson LLP
Associate Professor Mahesh Choolani

Head and Senior Consultant, Department of Obstetrics & Gynaecology,
Yong Loo Lin School of Medicine, NUS;
Chief and Senior Consultant, Department of Obstetrics & Gynaecology, NUH; and
Group Chief, Obstetrics & Gynaecology,
National University Health System (NUHS)
Professor Julian Savulescu

Chen Su Lan Centennial Professor in Medical Ethics, NUS;
Director, Centre for Biomedical Ethics,
Yong Loo Lin School Medicine, NUS; and
Uehiro Chair in Practical Ethics,
University of Oxford, United Kingdom
Associate Professor Tan Meng How

Associate Professor,
School of Chemical and Biomedical Engineering,
Nanyang Technological University (NTU)
Adjunct Associate Professor Tan Ee Shien

Head and Senior Consultant, Genetics Service, Department of Paediatrics Medicine; and
Director, National Expanded Newborn Screening Programme, Kandang Kerbau Women’s
and Children’s Hospital
Dr G. Owen Schaefer
Assistant Professor,
Centre for Biomedical Ethics,
Yong Loo Lin School of Medicine, NUS
3
INTERNATIONAL ADVISOR
Professor Kazuto Kato

Professor,
Department of Biomedical Ethics and Public Policy,
Graduate School of Medicine,
Osaka University,
SECRETARIAT
Adjunct Associate Professor (Dr) Raymond Chua Swee Boon

Deputy Director-General of Health, Health Regulation Group (DDGH(HReg)), MOH
Ms Rachel Chen
Director, Regulatory Policy and Legislation Division (RPL), MOH
Dr Tiong Wei Wei

Deputy Director, Biomedical Ethics Coordinating Office/ Precision Medicine and Research
Branch (DD(BECO/PM&R)), RPL, MOH
Dr Adrian Sim
Senior Assistant Director (SAD(BECO/PM&R)), RPL, MOH
Mr Louis Peter Hor

Senior Manager (BECO), RPL, MOH
Ms Nathira Shafeen
Manager (BECO), RPL, MOH
Ms Toh Si Min
Senior Executive, RPL, MOH
Ms Beatrice Lee
Health Policy Analyst (PM&R), RPL, MOH
Ms Sharon Shen
Executive (BECO), RPL, MOH
Ms Muthusubramanian Shruti
Executive (BECO), RPL, MOH
Dr Durkeshwari Anbalagan-Raj (until Mar 2023)

Senior Assistant Director (SAD(BECO/PM&R)), RPL, MOH
Dr Phua Zheng Yen (Dec 2022 until Nov 2023)

Research Fellow
4
BIOETHICS ADVISORY COMMITTEE
(1 JANUARY 2022 TO 31 DECEMBER 2024)
PATRON
Dr Tony Tan Keng Yam
Honorary Patron and Distinguished Senior Fellow, SMU; and
Former President of the Republic of Singapore
EMERITUS ADVISOR
Emeritus Professor Lim Pin
Emeritus Consultant, Division of Endocrinology, NUH; and
Emeritus Professor of Medicine, NUS
CHAIR
Emeritus Professor, Department of Orthopaedic Surgery, NUS; and Emeritus Consultant,
Division of Paediatrics Orthopaedics, NUH
DEPUTY CHAIRS
Professor Kon Oi Lian
Adjunct Professor, Duke-NUS Medical School
Mr Gregory Vijayendran
Senior Counsel and Partner, Rajah and Tann Singapore LLP
MEMBERS
Dr Chew Wei Leong

Associate Director (Genome Design) and Senior Research Scientist, Genome Institute of
Singapore; and Adjunct Assistant Professor, NUS
Professor Chin Jing Jih

Chairman, Medical Board; and Senior Consultant, Department of Geriatric Medicine,
Tan Tock Seng Hospital (TTSH)
Emeritus Professor Roy Joseph

Emeritus Consultant, Department of Neonatology, Khoo Teck Puat - National University
Children’s Medical Institute, NUH; and Director of the Paediatric Ethics Program,
Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, NUS
Associate Professor Lai Poh San

Associate Professor, Department of Paediatrics; and Deputy Chairman, Institutional
Biosafety Committee, NUS
Mr Charles Lim Aeng Cheng

Principal Senior State Counsel, Legislation Division, Attorney-General’s Chambers
5
Associate Professor Lim Tit Meng
Chief Executive, Science Centre Board
Dr Nazirudin Bin Mohd Nasir

Mufti, Office of the Mufti, Islamic Religious Council of Singapore (MUIS)
Associate Professor Ngiam Kee Yuan

Group Chief Technology Officer, NUHS; and Senior Consultant, Division of Thyroid and
Endocrine Surgery, NUH and Alexandra Hospital
Professor Vineeta Sinha

Professor, Department of Sociology, Faculty of Arts and Social Sciences, NUS
Professor Patrick Tan Boon Ooi

Senior Vice Dean (Research), Duke-NUS Medical School; Executive Director, Precision
Health Research Singapore (PRECISE); and Chief Scientific Officer, Genome Institute of
Singapore
Mr Tan Sze Yao

Director, Legal Office, MOH, Singapore
Ms Joyce Teo
Senior Health Correspondent, The Straits Times
Dr Voo Teck Chuan

Head, Office of Ethics in Healthcare, SingHealth
6
Table of Contents
Foreword .................................................................................................................................... 8
Executive Summary ................................................................................................................... 9
Chapter 1: Introduction ............................................................................................................ 11
Chapter 2: Legislative and Regulatory Frameworks for HNGE .............................................. 22
Chapter 3: General Ethical Principles in HNGE...................................................................... 33
Chapter 4: HNGE Techniques/Technologies and their Relationship with Gene and Cell
Therapies .................................................................................................................................. 38
Chapter 5: Potential Research and Clinical Applications Of HNGE and Current Established
Methods to Treat Diseases ...................................................................................................... 45
Chapter 6: Mosaicism, Off-Target Effects, and On-Target Undesirable Modifications ......... 58
Chapter 7: Safety and Long-Term Effects of HNGE............................................................... 63
Chapter 8: Procurement and Use of Human Embryos and Oocytes in HNGE Research ........ 71
Chapter 9: Equitable Access and Allocation of Resources ...................................................... 78
Chapter 10: Genetic Enhancement and the Effects on Society................................................ 82
Chapter 11: Governance and Framework Tools for HNGE .................................................... 89
Chapter 12: Conclusion............................................................................................................ 97
Glossary ................................................................................................................................. 102
7
FOREWORD
In recent years advances in Human Nuclear Genome Editing (HNGE) technologies

have resulted in the discovery of more precise tools that hold great promise in advancing human
biomedical research and clinical research, with the potential to improve human health. These
technologies can alter genetic material, which can lead to promising breakthroughs in the
treatment of genetic disorders, cancers, and infectious diseases. In biomedical research, HNGE
technologies can facilitate the study of gene function and disease mechanisms, and accelerate
drug discovery and personalised medicine. While the use of HNGE technologies in biomedical
research and potential clinical applications (i.e., non-heritable gene editing) can bring along
benefits, they also raise ethical concerns including unintended consequences and long-term
effects on individuals, social inequalities, and other issues on consent. In addition, potential
applications of HNGE technologies for genetic enhancement in areas such as conferring
resistance to diseases and enhancement of physical attributes and cognitive abilities (i.e.,
heritable gene editing) raise considerable ethical issues, such as unintended consequences to
future generations, shift in attitudes and behaviours towards reproductive choices, and
reduction of genetic diversity in human population. Hence, these issues warrant further review
by the Bioethics Advisory Committee (BAC).
2 Recognising the challenges, the BAC has developed this public consultation paper to
discuss and obtain feedback on the ethical issues arising from the use of HNGE technologies
in biomedical and clinical research and other potential clinical applications. Other concerns
such as mosaicism, off-target effects, long-term safety, equitable access, the broad effect of
genetic enhancement on society, and how the HNGE governance framework can be
implemented in Singapore are also discussed. The paper covers the ethical principles to guide
the ethical use of HNGE applications in human biomedical research, clinical research, and
clinical translation, such as respect for persons, solidarity, justice, proportionality,
sustainability, and other ethical considerations including inclusivity, transparency, and
responsible stewardship of science. The public consultation paper is an adapted version of the
final advisory report.
3 The views of the public, stakeholders, research institutions, and interested organisations
are important and will assist the BAC in developing recommendations in the final advisory
report to guide the academics, researchers, healthcare professionals, Clinical Ethics
Committees (CECs) and Institutional Review Boards (IRBs) on the ethical use of HNGE
applications in human biomedical research, clinical research, and healthcare.

Chair
Bioethics Advisory Committee
June 2024
8
EXECUTIVE SUMMARY
The main topics covered in the Public Consultation Paper (adapted from the advisory
report) include:
a. Mosaicism, Off-Target Effects, and On-Target Undesirable Modifications
2 While gene editing technologies, when used in a controlled manner, can enable
corrections to the genomic sequence to be carried out with precision to rectify or remove
mutations that could otherwise lead to adverse health conditions, such technologies could also
lead to unintended biological outcomes such as chromosomal mosaicism in embryos, and
undesirable consequences arising from off-target mutations and deletions. The Chapter
discusses the ethical principles of proportionality, sustainability, solidarity, and responsible
stewardship of science, the ethical issues of chromosomal mosaicism, off-target effects, and
on-target undesirable modifications, and their impact to individuals and the society, which
would be important considerations for potential applications of HNGE.
b. Safety and Long-Term Effects of HNGE
3 While gene editing offers new ways of treating diseases and may potentially be used
for enhancement of human performance, it has yet to receive general acceptance for widespread
use in clinical practice. This is because the technology is still in its early stage of development,
which raises concerns regarding the safety and long-term side effects of the technology on
individuals receiving the treatment. The Chapter discusses the ethical principles of
proportionality, sustainability, and responsible stewardship of science, and the ethical issues
of long-term side effects and consequences of non-heritable and heritable gene editing. It also
discusses the management of these consequences through long-term follow-up and
intergenerational monitoring of patients involved in potential interventions of HNGE by
researchers and healthcare professionals.
c. Procurement and Use of Human Embryos and Oocytes in HNGE Research
4 Human embryos have been used by researchers on gene editing as a tool to enhance
knowledge about human gene function and early embryonic development, as well as to advance
research on infertility, genetic diseases, and intractable diseases. While procuring oocytes with
the desired genotype from healthy individuals can enable researchers to study gene mutations
in oocytes for a given disease-causing gene, or to correct a specific gene mutation, it may lead
to health risks for donors. The Chapter provides an overview on the 14-day limit for embryo
research, the different types of embryos used in HNGE research, and discusses the ethical
issues involved in the procurement and use of embryos and oocytes in gene editing research.
These include health risks to donors and potential breach of privacy and confidentiality of
donors’ genomic data. The Chapter also discusses the relevant ethical principles of respect for
persons, justice, proportionality, and transparency which researchers and research institutions
should consider in ensuring the autonomy and well-being of oocyte donors are respected, and
enhance transparency in the research process.
d. Equitable Access and Allocation of Resources
5 Gene editing technologies extend beyond discovering and developing therapies,

particularly for rare genetic disorders, severe diseases such as cancer and treatment of infertility.
9
These technologies can potentially be used for enhancing specific traits. However, as with
many new modalities in medicine, gene editing technologies also give rise to concerns such as
inequitable access by those who are in need but cannot afford them. The Chapter deliberates
the potential issues arising from the inaccessibility of HNGE technologies for clinical
applications due to high costs and under-representation of the Asian population in clinical data
involving HNGE research. The Chapter also discusses the applicable ethical principles of
justice and inclusivity that researchers and research institutions should consider when
improving gene editing for use in research and clinical applications and designing clinical trials
for HNGE research.
e. Genetic Enhancement and the Effects on Society
6 Recent advances have increased the possibility that gene editing can be used for
purposes that go beyond therapies and medical interventions, and the possible applications of
gene editing technologies include genetic enhancement in areas such as conferring resistance
to diseases and enhancement of physical attributes and cognitive abilities. Such potential
clinical applications of gene editing technologies raise several ethical issues. The Chapter
discusses the ethical issues involved in applications of gene editing technologies for genetic
enhancement, including the unintended consequences, social inequity, shift in attitudes and
behaviours towards reproductive choices, and reduction of genetic diversity in human
population. The Chapter also discusses the relevant ethical principles of proportionality,
sustainability, justice, inclusivity, transparency, and responsible stewardship of science that
researchers, research institutions, and IRBs should consider for applications of gene editing
technologies for enhancement if permitted in the future.
f. Governance and Framework Tools for HNGE
7 As with other technological advances, gene editing raises ethical and social issues that
must be addressed through having proper governance frameworks in place. The Chapter
discusses the governance and regulatory frameworks for HNGE at the following respective
levels: (i) institutional research level; (ii) clinical trials level; and (iii) national level. The
Chapter also discusses the different tools and approaches to strengthen existing research
governance frameworks, which include (i) professional self-regulation; (ii) providing
education and training on HNGE for researchers and clinicians; (iii) reinforcement of
institutional practices; (iv) setting up of HNGE registries; (v) whistleblowing mechanisms; and
(vi) other international mechanism(s) for reporting unethical HNGE experiments.
The Executive Summary of recommendations

will be included in the final advisory report.
10
CHAPTER 1: INTRODUCTION
Human Nuclear Genome Editing (HNGE)
1.1 The human genome, made of deoxyribonucleic acid (DNA), contains all the information
needed for an individual to develop and function. (Fig 1.1). As the cells in the body replicate,
genetic mutations/changes can occur to the nucleotide sequences of the DNA, which can
lead to changes in protein structure and cell function. Such genetic mutations could either
lead to genetic conditions such as cancer or they could help humans better adapt to their
environment over time. In cases where genetic mutations lead to genetic diseases, gene
editing has the potential to treat such diseases. Gene editing is a group of technologies that
enable scientists to change an organism’s DNA by adding, removing or altering genetic
material at particular locations in the genome (Fig 1.1). Gene editing tools allow for a
harmful DNA variant to be edited to a healthy variant, which could potentially prevent or
cure a genetic disease, hence displaying great potential for breakthroughs in medical
treatments. 1 Therefore, researchers have shown great enthusiasm in developing new
technologies in therapeutic gene editing over the years.
Figure 1.1: Diagram portraying the relationship between Genes, Genomes, DNA,
Nucleotides, and the role of Gene Editing
1.2 Scientists use different technologies to make changes to the DNA. These technologies act
like scissors, cutting the DNA at a specific spot before scientists remove, add, or replace the
DNA where it was cut. The first attempts at gene editing occurred in the 1980’s, and
subsequently, many researchers tried to develop methods to edit specific gene. 2 New
genomic tools have made it easier than ever to edit DNA, where they have enabled DNA to
be edited in a simpler, faster, cheaper, and more accurate manner, such that the desired
1
U.S. National Library of Medicine. (n.d.). What are genome editing and CRISPR-Cas9? MedlinePlus.
https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/ Retrieved on 2 August 2023.
2
Matsumoto, D. & Nomura, W. (2023). The History of Genome Editing: Advances from the Interface of
Chemistry & Biology. Chemical Communications, 59, 7676 – 7684. https://doi.org/10.1039/D3CC00559C.
11
outcome is achieved with minimal off-target effects. Gene editing tools also have the
potential to diversify scientists’ knowledge in genetics by generating cellular models, which
can mimic various human diseases to better understand disease consequences and develop
new treatments.
1.3 Human nuclear genome editing (HNGE) may be broadly classified into: (a) non-heritable
gene editing; (b) heritable gene editing for clinical applications; and (c) gene editing in
embryos or germline cells for research.
a. Non-heritable (or somatic) gene editing is carried out in cells that are unable to or do
not contribute to gamete formation, which are responsible for generation of
reproductive cells.3 As such, changes made to these cells cannot be inherited by the
offspring of the individual receiving the treatment. Common applications of non-
heritable gene editing include clinical treatment of genetic disorders in individuals with
cystic fibrosis 4 and severe combined immunodeficiency (SCID) syndrome, 5 or for
research purposes.
b. Heritable gene editing for clinical applications involves gametes (eggs or sperm),
germline cells or early-stage embryos with the intent of transferring any resultant
embryos to a woman’s uterus for gestation. 6 Edits to the genome may be made for
purposes of treatment of diseases, conferring resistance against diseases, or
enhancement of traits by making changes to the genetic material of gametes, or any
precursor cells that lead to their development, which include the cells of early embryos.
The genetically modified embryos are then transferred into a uterus to initiate and
establish a pregnancy that would result in the birth of a child with modified genome.
When the child reaches the age capable of producing gametes, such genetic edits made
to these cells will be inherited by the progeny and passed down to future generations.
c. Gene editing may also be applied on germline cells or embryos for research. It can be
used in reproductive medicine to correct mutations in germ cells in testes or ovaries, or
in germ cells used to derive gametes in vitro for studies involving cellular development.
Progenitor cells of gametes can also be isolated and genetically modified in vitro but
are not implanted into a human body for establishing pregnancy. For instance, missense
mutations in regulator genes in oocytes that may impede oocyte maturation or early
embryonic developmental arrest and lead to failure of fertilisation, may be corrected to
recover the oocytes’ developmental potential and enable higher chances of successful
3
National Academy of Sciences, National Academy of Medicine, National Academies of Sciences, Engineering,
and Medicine, & Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations.
(2017). Human genome editing: Science, ethics, and governance. National Academies
Press. https://www.ncbi.nlm.nih.gov/books/NBK447271/ Retrieved on 2 August 2023.
4
Hodges, C. A., & Conlon, R. A. (2019). Delivering on the promise of gene editing for cystic fibrosis. Genes &
Diseases, 6(2), 97–108. https://doi.org/10.1016/j.gendis.2018.11.005
5
Fischer, A., & Hacein-Bey-Abina, S. (2019). Gene therapy for severe combined immunodeficiencies and
beyond. Journal of Experimental Medicine, 217(2). https://doi.org/10.1084/jem.20190607
6
Baylis, F., Darnovsky, M., Hasson, K., & Krahn, T. M. (2020). Human Germline and Heritable Genome Editing:
The Global Policy Landscape. https://www.liebertpub.com/doi/10.1089/crispr.2020.0082 Retrieved on 2 August
2023.
12
pregnancy. 7 In azoospermia patients that suffer from a chromosomal mutation that
causes meiotic arrest of sperm cells, spermatogonial stem cells (SSC) may also be
genetically corrected in infertile males. 8 However, this investigative therapy is
currently in its experimental phase and further studies are necessary to warrant any
translational applications as changes that are theoretically present in the germ cells can
potentially be passed on.
Global and Local Trends on the Use of HNGE in Human Biomedical Research and
Clinical Applications
1.4 Over the years, gene editing has witnessed a paradigm shift with the advent of techniques
in gene editing involving the clustered regularly interspaced short palindromic repeats-
CRISPR-associated protein 9 (CRISPR-Cas9), zinc-finger nucleases (ZFNs) and
transcription activator-like effector nucleases (TALENs).9 These enzymatic tools share a
common characteristic of changing the DNA sequences within the genome through
leveraging a combination of programmable targeting of specific sites, inducing DNA breaks,
inserting DNA, deleting DNA, modifying the chemical identity of nucleotides, and/or
harnessing the endogenous repair mechanism within the cell. Such changes can repair gene
mutations associated with diseases. Further advancements in gene editing methods have also
enhanced knowledge in human genetics, epigenetics, molecular biology, and pathology,
enabling disease modeling and drug discovery to be made more viable. As such, gene
editing-mediated trials have led to positive treatment outcomes in patients with
haematological diseases, such as sickle cell disease10 and thalassaemia.11 Nonetheless, as
the sample sizes in these trials were small, and follow-up duration could be short, a larger
sample size and long-term follow-up would be required to accurately assess the long-term
effects or sustainability of outcomes.
1.5 Moreover, the increasing prevalence of infectious diseases, cancer and genetic disorders
have bolstered advancement of medical science which in turn is driven by the demand for
personalised medicine.12 To personalise treatments for patients, substantial understanding
of the factors contributing to the health and disease of the person is necessary. This includes
analysing the molecular dynamics of the cell at the genetic level to diagnose the status of
disease as well as predicting treatment outcomes from biomarkers. For example, CRISPR
7
Fei, C., & Zhou, L. (2022). Gene mutations impede oocyte maturation, fertilization, and early embryonic
development. BioEssays, 44(10), 2200007. https://doi.org/10.1002/bies.202200007
8
Tong, M.-H., Li, J.-S., Wang, Y.-H., Yan, M., Zhang, X., Liu, X.-Y., Ding, Y.-F., & Lai, C.-P. (2021). Rescue
of male infertility through correcting a genetic mutation causing meiotic arrest in spermatogonial stem cells. Asian
Journal of Andrology, 23(6), 590. https://doi.org/10.4103/aja.aja_97_20
9
Zhou, W., Yang, J., Zhang, Y., Hu, X., & Wang, W. (2022). Current landscape of gene‐editing technology in
Biomedicine: Applications, advantages, challenges, and perspectives. MedComm, 3(3).
https://doi.org/10.1002/mco2.155
10
Zarghamian, P., Klermund, J., & Cathomen, T. (2023). Clinical genome editing to treat sickle cell disease—a
brief update. Frontiers in Medicine, 9. https://doi.org/10.3389/fmed.2022.1065377
11
Rahimmanesh, I., Boshtam, M., Kouhpayeh, S., Khanahmad, H., Dabiri, A., Ahangarzadeh, S., Esmaeili, Y.,
Bidram, E., Vaseghi, G., Haghjooy Javanmard, S., Shariati, L., Zarrabi, A., & Varma, R. S. (2022). Gene editing-
based technologies for beta-hemoglobinopathies treatment. Biology, 11(6), 862.
https://doi.org/10.3390/biology11060862
12
Ho, D., Quake, S. R., McCabe, E. R. B., Chng, W. J., Chow, E. K., Ding, X., Gelb, B. D., Ginsburg, G. S.,
Hassenstab, J., Ho, C.-M., Mobley, W. C., Nolan, G. P., Rosen, S. T., Tan, P., Yen, Y., & Zarrinpar, A. (2020).
Enabling technologies for personalised and precision medicine. Trends in Biotechnology, 38(5), 497–518.
https://doi.org/10.1016/j.tibtech.2019.12.021
13
and other gene-editing tools have demonstrated promise of repairing defective genes found
in patients with severe diseases ranging from acquired cancer to inherited genetic diseases.
The growth of gene editing market is further driven by the increasing need for funding and
initiatives by the government to develop complementary markets in vaccines, medical
technologies, drugs as well as devices.
1.6 Currently, non-heritable gene editing is being explored in human biomedical research and
clinical applications for a wide genre of diseases, from HIV to muscular dystrophy and even
coronavirus disease 2019 (COVID-19).13 Gene editing in embryos or germline cells is also
carried out through properly regulated research purposes. The outcome may hold promise
for the treatment and prevention of more complex diseases. Heritable gene editing in clinical
application, however, is strictly prohibited in most countries. This includes Canada,
Australia, and Europe, where any form of research involving germline gene editing is
banned.14
1.7 The gene editing market is dominated by North America due to the strong growth trend in
the pharmaceutical and biotechnology industries, technological innovation in gene editing
technologies, increasing product approvals, as well as the rising number of clinical trials
conducted for gene editing. For example, in March 2021, scientists at the University of
California (UC) San Francisco, UC Berkeley, and UC Los Angeles received approval from
the United States Food and Drug Administration (FDA) to jointly launch an early phase,
first-in-human clinical trial of a gene correction therapy in patients with sickle cell disease
using the patient’s blood-forming stem cells. 15 The trial combined CRISPR technology
developed at the Innovative Genomics Institute (IGI), founded by Nobel Laureate Jennifer
Doudna, and expertise at UCSF Benioff Children’s Hospital Oakland in cord blood and
marrow transplantation and in gene therapy for sickle cell disease.
1.8 In Europe, the United Kingdom (UK) has been contributing significantly to the growth of
the gene editing market due to the rising geriatric population and increasing incidence of
chronic diseases. The use of gene editing to treat children with severe diseases such as cystic
fibrosis, muscular dystrophy and Tay-Sachs has also received great support based on the
results from surveys conducted.16 While it is illegal to edit embryonic genomes meant for
pregnancies, younger generations have shown greater support for designer babies and that
the ban could be lifted if it is demonstrated that the procedure can safely prevent severe
diseases.
1.9 The Asia Pacific gene editing market has also been growing exponentially due to the rising
geriatric population, modernisation of healthcare practices, technological advancements,
and government initiatives for controlling diseases. For instance, in March 2021, scientists
13
Collins, F. (n.d.). Non-heritable gene editing. National Institutes of Health.
https://directorsblog.nih.gov/tag/non-heritable-gene-editing/ Retrieved on 2 August 2023.
14
Gyngell, C. (2017). Gene editing and the health of future generations. Journal of the Royal Society of
Medicine, 110(7), 276–279. https://doi.org/10.1177/0141076817705616
15
Fernandes, L. (2021) UC Consortium Launches First Clinical Trial Using CRISPR to Correct Gene Defect That
Causes Sickle Cell Disease | UC San Francisco. https://www.ucsf.edu/news/2021/03/420137/uc-consortium-
launches-first-clinical-trial-using-crispr-correct-gene-defect Retrieved on 2 August 2023.
16
Sample, I. (2022). Half in UK back genome editing to prevent severe diseases. The Guardian.
https://www.theguardian.com/science/2022/jun/22/half-in-uk-back-genome-editing-to-prevent-severe-diseases
Retrieved on 2 August 2023.
14
from the Genome Institute of Singapore (GIS) developed a novel CRISPR-based gene editor,
C-to-G base editor (CGBE), to correct mutations that lead to genetic disorders.17 CGBE is
a CRISPR-based gene editor which allows substitution of a single base in faulty genomic
sequences responsible for diseases such as cystic fibrosis, cardiovascular diseases,
musculoskeletal diseases and neurological disorders.
Advantages and Disadvantages of Non-Heritable Gene Editing, Heritable Gene Editing

for Clinical Applications and Gene Editing in Embryos or Germline Cells for Research
Purposes
a. Advantages and Disadvantages of Non-Heritable Gene Editing
1.10 Non-heritable gene editing offers the primary advantage of delivering new treatments or
cures for diseases by changing disease-causing genetic mutations solely within somatic cells.
This reduces the risk of propagating, particularly potentially detrimental, edit-related
changes to future generations. However, the potential high costs of subscribing to non-
heritable gene editing as a therapy may prove to be unaffordable and inaccessible for many
people.
1.11 In addition, when gene editing does not occur accurately, the off-target effects can result in
unintended edits, which is an important risk to consider. Unintended edits (mutations) may
occur in a subset of cells during gene editing. When these group of cells include important
genes, such mutations could lead to harmful effects such as cancer. However, the probability
of off-target effects varies according to the design of the gene editing technologies and is
often quantified with stringent genomic sequencing. Hence, the off-target effect is an
important factor to consider when weighing the benefits and risks of each gene editing
treatment.
1.12 Compared to heritable gene editing, non-heritable gene editing may exhibit lower editing
efficiency and therapeutic outcome. This is because while heritable gene editing ensures
that all cells of future offspring inherit the edited genomic sequence(s), non-heritable gene
editing often results in genetic mosaicism, where only a fraction of the cells is edited with
the desired sequences while other cells comprise of unedited or unintendedly edited
genomes. This could lead to a non-homogeneous population of cells which may be
insufficient to elicit the desired treatment response. Ongoing advances in more efficient and
precise gene editing technology could enhance the efficacy of non-heritable gene editing.
b. Advantages and Disadvantages of Heritable Gene Editing for Clinical

Applications
1.13 Heritable gene editing used for clinical applications could enable correction of disease-
causing mutations to be passed on from generation to generation and prevent the disease
from developing in subsequent generations. Such applications could also enable conferring
of resistance or enhancement of traits that is inheritable in future generations. However,
unintended edits introduced during genetic modifications may similarly be passed down to
future generations and bear potential negative effects on offspring. For instance, off-target
effects due to DNA double strand breaks at the wrong sites because of imprecision in edits
17
ASTAR. (n.d.). Singapore scientists develop novel gene editor to correct disease. https://www.a-
star.edu.sg/News/astarNews/news/press-releases/singapore-scientists-develop-novel-gene-editor-to-correct-
disease-causing-mutations-into-healthy-versions Retrieved on 2 August 2023.
15
made have been reported in human zygotes.18 Similar to that of non-heritable gene editing,
genetic mosaicism was observed in the same study as well, urging caution and the need for
further studies of heritable gene editing for clinical applications (discussed in Chapter 6).
The cost of receiving germline gene editing therapies may also be high given the
sophisticated technology involved and therefore become unaffordable and inaccessible for
many, potentially aggravating issues arising from societal inequality (discussed in Chapter
10).
1.14 Heritable gene editing may also be used to enable pregnancy by correcting mutations in
germ cells, such as oocytes and spermatogonial cells, to potentially treat male and female
infertility. This would allow parents with inherent difficulties in fertility to bear and have
their own children without receiving gametes from others, which would pose possible legal
implications pertaining to the custodial rights of the child born (discussed in Chapter 5).19
Nonetheless, when mutations are introduced at the wrong site of the DNA in germline cells
during the process of germline gene editing, such errors introduced in editing could possibly
lead to unknown ramifications with severe consequences, adversely affecting individuals
receiving the treatment as well as their future progeny.
c. Advantages and Disadvantages of Gene Editing in Embryos or Germline Cells for

Research Purposes
1.15 Gene editing carried out in embryos or germline cells for research allows researchers to
advance scientific research including those on clinical applications involving heritable gene
editing and promote understanding of human embryonic development. However, the
procurement of human embryos for research purposes would be difficult due to risks
involved for the donor. Furthermore, human embryos could be destroyed during, or after
use for research, raising ethical dilemmas including non-maleficence and concerns
pertaining to justice. To ensure that germline gene editing research is conducted ethically,
the BAC adopts the following positions: (i) specific and personal consent from the donors
must be obtained before any oocytes or embryos are used for research; (ii) potential donors
should be provided with sufficient information and time to make an informed decision; (iii)
for women undergoing fertility treatment, consent for donation of surplus oocytes or
embryos should be separate from the consent of treatment; (iv) the treating physician should
not also be the researcher seeking consent for the donation of eggs and embryos for research;
and (v) as the process for donating eggs for research is time-consuming, invasive, and
associated with a certain degree of discomfort and risk, women who wish to donate eggs
specifically for research must be interviewed by an independent panel. The panel must be
satisfied that they are of sound mind, clearly understand the nature and consequences of the
donation, and have freely given explicit consent, without any inducement, coercion, or
undue influence.20
1.16 Research and clinical applications of non-heritable and heritable gene editing, and gene
editing in embryos or germline cells for research, should be properly and carefully assessed
18
Liang, P. et al. (2015) ‘CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes’, Protein & Cell,
6(5), pp. 363–372. doi:10.1007/s13238-015-0153-5.
19
Rubeis, G., & Steger, F. (2018). Risks and benefits of human germline genome editing: An ethical
analysis. Asian Bioethics Review, 10(2), 133–141. https://doi.org/10.1007/s41649-018-0056-x.
20
Bioethics Advisory Committee Singapore (2021). Ethics Guidelines for Human Biomedical Research (2021
Revised). Sections 5.25-5.29. https://www.bioethics-singapore.gov.sg/publications/reports/bac-ethics-guidelines-
2021 Retrieved on 2 August 2023.
16
prior to approval, due to the known and unknown risks of gene editing technology. A known
risk is off targeting, where unintended edits can occur in genes. However, as with any new
and evolving technology, there may be unforeseen risks that only become apparent over
time. It can take many years to fully determine the spectrum of risks associated with gene
editing. Clinical studies are one of the key instruments intended to uncover these potential
long-term and unforeseen effects. Therefore, with technological advancements, continual
evaluation is crucial to ensure a well-informed risk-benefit consideration. Such risk-benefit
consideration may allow for the research and clinical applications of non-heritable gene
editing to be conducted, if the benefits of the therapy outweigh the risks as well as other
possible negative consequences as a result of unintended mutations.
1.17 Nonetheless, heritable gene editing for treatment of diseases, conferring resistance, or
enhancement of traits, should not be recommended until safety, efficacy and long-term
effects are well established. This is because the mutations can be passed down to the future
generations, and the unknown negative effects that could arise because of the errors in
editing could outweigh the possible benefits of the therapy. This is especially relevant if the
technologies are used to confer resistance to diseases or enhance certain traits which can
cause potential harm to the future generations. Most jurisdictions and international bodies
such as the World Health Organization (WHO), scientific and professional societies such as
the International Society for Stem Cell Research (ISSCR), either recommends changes in
policy and practice to support the reporting of possible heritable gene editing or does not
recommend the use of heritable gene editing.
1.18 Heritable gene editing for infertility should be prohibited until the safety, efficacy and long-
term effects are well established. This is because ooplasmic transfer and pronuclear transfer
have only been practised for treating intractable infertility in some countries such as the UK
to prevent the inheritance of pathogenic mitochondrial DNA mutations in offspring. 21
Furthermore, off-target effects arising from heritable gene editing can affect future progeny
and could also harm the individuals undergoing the treatment when modifications to the
genome is made at the wrong site.
1.19 However, gene editing in embryos or germline cells for research may be allowed if the
research on human embryos is conducted before the 14th day of their creation. This practice
is uniformly regulated across countries given that the embryos were a collection of cells
shown to sustain in vitro for 12 - 13 days after fertilisation for research purposes.22 The
Warnock Committee’s stand was premised on the view that only after the 14th day, the
embryo would be considered as an individual and potential person with rights to life.23
Ethical Issues Arising from Heritable Gene Editing and Human Embryo Research
1.20 Heritable gene editing could result in inaccurate editing such as off-target effects and genetic
mosaicism, both of which could result in increased risk of heritable genetic diseases for
future progeny. As such the welfare of future offspring or children may be jeopardised
21
Ishii, T., & Hibino, Y. (2018). Mitochondrial manipulation in fertility clinics: Regulation and
responsibility. Reproductive Biomedicine & Society Online, 5, 93–109.
https://doi.org/10.1016/j.rbms.2018.01.002
22
Blackshaw, B. P., & Rodger, D. (2021). Why we should not extend the 14-Day rule. Journal of Medical
Ethics, 47(10), 712–714. https://doi.org/10.1136/medethics-2021-107317
23
Bruce, P., and Daniel, R. (2021). Why we should not extend the 14-day rule. Journal of Medical Ethics, 47(10),
712 – 714. doi:10.1136/medethics-2021-107317.
17
(principle of sustainability) and further complications for the prospective mother such as
psychological distress and infertility (principle of non-maleficence) may also arise. There is
also a lack of sufficient preclinical studies and clinical trials demonstrating the safety and
efficacy of heritable gene editing (principles of beneficence, non-maleficence, and
responsible stewardship of science) given the relative infancy of the technology. The
difficulty in predicting potential harmful side-effects that could occur because of heritable
gene editing and possible interactions of such resultant genetic changes with other genes or
the environment could render future offspring or children susceptible to unknown long-term
side effects. These genetic alterations may continue to occur and be introduced to the
population which can be difficult to ameliorate (principle of sustainability).
1.21 Extending the duration in which gene editing on germ line cells and human embryos could
be conducted (i.e., beyond 14 days) could facilitate further development of heritable gene
editing, but potentially risk leading to their misuse (principle of justice). Oocyte
procurement for gene editing in embryos or germline cells for research is also physically
invasive which could pose significant risks to the health or life of the donor (principle of
non-maleficence).
1.22 Furthermore, heritable gene editing for enhancement could exacerbate social inequities,
resulting in skewed societal expectations of abilities and traits that are considered ideal, as
well as aggravating inequitable access to germline gene therapy. As a result, the technology
may be used by consumers in a coercive environment, such as that under societal pressure
(principles of justice and sustainability). Heritable gene editing for enhancement could also
result in the permanent removal of beneficial characteristics important for survival, hence
posing harm to the offspring (principles of justice and sustainability). The general ethical
principles of HNGE will be discussed in Chapter 3.
Issues that could Arise when Ethics is not Incorporated to the Conduct of Human
Biomedical Research/Clinical Applications Involving HNGE
1.23 The CRISPR babies scandal constitutes the most notable instance in which heritable gene
editing in human embryos has drawn strong criticism from the scientific and medical
communities. 24 In 2018, Chinese scientist He Jiankui applied germline gene editing to
several human embryos which resulted in the birth of two genetically modified babies. By
doing so, he flouted established norms for safety and human protection. With the claimed
purpose of introducing the uncommon ability to resist infection from HIV, he tried to
reproduce the phenotype of a specific mutation in the gene CCR5. However, He generated
a frameshift mutation intended to make the CCR5 protein entirely nonfunctional instead of
introducing the known mutation.
1.24 He Jiankui’s CRISPR experiment has garnered widespread attention and controversy which
could shape research involving gene editing in humans for years to come, such as:
a) increased interest in research studies on non-heritable gene editing as researchers
become cautious of conducting research in gene editing on germline cells;
24
Guardian News and Media. (2018, November 26). World’s first gene-edited babies created in China, claims
scientist. The Guardian. https://www.theguardian.com/science/2018/nov/26/worlds-first-gene-edited-babies-
created-in-china-claims-scientist Retrieved on 2 August 2023.
18
b) further tightening of regulations and guidelines25 on gene editing in germline cells (and
incidentally, non-heritable gene editing) due to additional caution practised by the
scientific community, which could stifle developments in HNGE; and
c) adversely impacting the growth of gene editing in germline cells for research26 such as
the number of researchers working in the field, research output and funding, despite the
benefits that may be harnessed from such research if conducted ethically.
1.25 Following He Jiankui’s CRISPR baby scandal, there were several instances of similar
studies involving gene editing carried out on germline cells or human embryos that triggered
warnings from bioethicists. For example, several groups from China,27 and the United States
of America (US) have published results of similar experiments in the next two years
following the scandal, and the studies went from using non-viable embryos to using ones
that could conceivably be implanted. Separately, a study conducted in the US in 2017
verified the gene editing ability of CRISPR-Cas9 to correct mutations associated with
genetic disease using human embryos.28 While research works carried out in this area have
prompted the need for caution, scientists anticipate clinical applications as a possible
outcome arising from these studies.29 Therefore, it is important to carefully consider the
ethical, social, and legal implications involved in gene editing and put in place relevant
regulatory tools and governance framework to prevent subsequent research from being
carried out unethically.
Other Challenges
1.26 Besides ethical issues and considerations, there are other challenges faced, particularly in
the clinical translation of heritable gene editing where it is often difficult to delineate clinical
applications from clinical research. Established clinical translation pathway for new
therapies (i.e., multistage controlled trial system to determine safety and efficacy of a tested
treatment) is not applicable for heritable gene editing, as clinical trials involving heritable
gene editing cannot be considered a controlled study design since there are no suitable
controls for comparison. Exploratory trials (i.e., phase zero or phase one) that carries out
microdosing of a new drug in a small number of patients to establish its safety would not be
suitable for heritable gene editing studies. In standard first-in-human trials, an administered
drug can be withdrawn instantaneously after the emergence of adverse effects, and if
necessary, treatments can possibly be provided to counter adverse effects. However, these
options do not exist for clinical trials involving heritable gene editing, as the intervention
cannot be reversed when a genetically modified embryo has been implanted into the uterus.
Therefore, this report will not discuss the ethical issues arising from clinical trials involving
25
Zhang, J. Y., & Lei, R. (2023, March 10). Is Chinese bioethics ready to move forward from the CRISPR baby
scandal? The Hastings Center. https://www.thehastingscenter.org/is-chinese-bioethics-ready-to-move-forward-
from-the-crispr-baby-scandal/ Retrieved on 2 August 2023.
26
Cyranoski, D. (2020, January 6). What CRISPR-baby prison sentences mean for research. Scientific American.
https://www.scientificamerican.com/article/what-crispr-baby-prison-sentences-mean-for-research/ Retrieved on
2 August 2023.
27
Niemiec, E., & Howard, H. C. (2020). Ethical issues related to research on genome editing in human
embryos. Computational and Structural Biotechnology Journal, 18, 887–896.
https://doi.org/10.1016/j.csbj.2020.03.014
28
Cha, A. E. (2021). First human embryo editing experiment in U.S. “corrects” gene for heart condition. The
Washington Post. https://www.washingtonpost.com/news/to-your-health/wp/2017/08/02/first-human-embryo-
editing-experiment-in-u-s-corrects-gene-for-heart-condition/ Retrieved on 2 August 2023.
29
Lim, J. and Kim, H. (2022) ‘Basic principles and clinical applications of CRISPR-based genome
editing’, Yonsei Medical Journal, 63(2), pp. 105–113. doi:10.3349/ymj.2022.63.2.105.
19
heritable gene editing, as they would be similar to the ethical issues and considerations
arising from clinical applications of heritable gene editing.30
Overview of Legislations and Regulatory Frameworks Governing HNGE
1.27 Most countries have put in place legislations that prohibit the use of heritable gene editing,
such as Australia, Germany, and Korea, while others such as the UK, the US, Japan and
Singapore, have conditionally allowed the use of gene editing in embryos or germline cells
for research purposes under strict regulations. For instance, Australia’s ‘Prohibition of
Human Cloning for Reproduction Act (2002, as amended 2017)’ prohibits heritable
alterations to the genome. Germany’s ‘Embryo Protection Act (1990, as amended 2011)’
punishes anyone who artificially alters the genetic information of a human germline cell, or
anyone who uses a human germ cell with artificially modified genetic information for
fertilisation. Authorities in Japan have also issued guidelines to restrict the use of human-
fertilised embryos for basic research employing gene editing.31 While Singapore does not
have any specific legislation on gene editing, Singapore’s ‘No. S 622 Human Biomedical
Research (Restricted Research) Regulations 2017’ states that every research institution and
researcher conducting restricted research must ensure that restricted research carried out
does not involve a human embryo which is more than 14 days old from the time of creation
of the embryo (excluding any period when the development of the embryo is suspended).
The Regulations also state that the research institution and the researcher must ensure that
only surplus embryos created in assisted reproduction treatment may be used for research.
1.28 Most international guidelines recommend against the use of illegal and unsafe heritable gene
editing. For instance, the WHO Expert Advisory Committee on Developing Global
Standards for Governance and Oversight of Human Genome Editing developed new
advisory guidelines in 2021 which recommend the changes in policy and practice to support
the reporting of possible illegal, unregistered, unethical, or unsafe non-heritable gene editing,
heritable gene editing and gene editing in embryos or germline cells for research.32
1.29 Most scientific and professional societies do not recommend the clinical use of heritable
gene editing but allow gene editing in embryos or germline cells for research. The
International Society for Stem Cell Research (ISSCR) Guidelines (2021) does not
recommend that heritable gene editing should be pursued at this time as approaches are
currently unsafe or raise unresolved ethical issues. Additionally, it recommends that gene
editing in embryos or germline cells for research should be allowed only after review and
approval through a specialised scientific and ethics review process. International medical
associations such as the World Medical Association issued a statement on human gene
30
Rosemann, A, Balen, A, et. al. (2019). Heritable Genome Editing in a Global Context: National and
International Policy Challenges. The Hastings Center Report. 49(3), pp 30 – 42. https://doi.org/10.1002/hast.1006.
31
Public Notice of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Ministry of
Health, Labor and Welfare (MHLW) (2019). Guidelines for research using gene-altering technologies on human
fertilized embryos are established as follows, and shall come into force as from the date of
promulgation. https://www.lifescience.mext.go.jp/files/pdf/Overview_Human_embryo_geneome-
editing_guideline2019En.pdf Retrieved on 17 January 2024.
32
World Health Organization. (2021). Who expert advisory committee on developing global standards for
governance and oversight of human genome editing: Report of the Sixth meeting.
https://www.who.int/publications/i/item/who-expert-advisory-committee-on-developing-global-standards-for-
governance-and-oversight-of-human-genome-editing-report-of-the-sixth-meeting Retrieved on 2 August 2023.
20
editing that non-heritable gene editing should be implemented according to appropriate
evidence that is collected via well-conducted and ethically approved research studies.
Objective of this Advisory Report
1.30 To address the emerging ethical, legal, and social implications of HNGE in biomedical
research, the BAC has developed an advisory report and recommendations to guide
researchers, academics, healthcare professionals, Institutional Review Boards (IRBs), and
other ethics committees such as the Clinical Ethics Committees (CECs) on the ethical use
of HNGE in biomedical research. While there are other pre-existing reports from the WHO
and other global organisations or committees on this topic, the HNGE advisory report serves
to guide the national ethical framework for HNGE in Singapore and provide BAC’s
recommendations to inform the Singapore government on policy decisions. The advisory
report will also serve as a useful reference for local and overseas bioethics counterparts to
understand Singapore’s position on HNGE.
21
CHAPTER 2: LEGISLATIVE AND REGULATORY FRAMEWORKS FOR HNGE
2.1 In the realm of gene editing, a complex landscape of legislation and guidelines has emerged
to navigate the ethical, legal, and social implications of gene editing technologies. These
legislation and guidelines seek to balance the potential benefits of gene editing with
concerns surrounding safety, informed consent, and equity. The first part of this chapter
provides an overview of the legislation for HNGE, including those for (i) non-heritable gene
editing for research and clinical applications, and for (ii) heritable gene editing for clinical
applications and gene editing in embryos and germline cells for research. The second part
of this chapter provides an overview of the guidelines available to guide the ethical
applications of HNGE, and discusses the different guidelines that (i) explicitly recommend
against heritable gene editing for clinical applications; and (ii) recommend heritable gene
editing for clinical applications on conditions.
I. Local Legislation for HNGE
i. Non-Heritable Gene Editing (for research and clinical applications)

2.2 Non-heritable gene editing is generally allowed for research purposes in Singapore, but
approval is required from the Institutional Review Boards (IRBs) and detailed and informed
consent needs to be obtained from participants. The use of gene editing products for
innovative salvage therapy, which is the offering of an untested practice when conventional
therapy has proven to be unhelpful under desperate or dire circumstances, is also allowed.1
However, the prescribed treatment must first be reviewed by the relevant Clinical Ethics
Committee (CEC) as ethically appropriate.
a. Human Biomedical Research Act 2015
2.3 Currently, the use of non-heritable gene editing for research is not prohibited or restricted
under the Human Biomedical Research Act 2015. As such, non-heritable genome editing
for research purposes is permitted in Singapore.
b. Health Products Act 2007
2.4 Therapeutic products and active ingredients used in the manufacture of cell, tissue, and gene
therapy products (CTGTP) are regulated under the Health Products Act 2007 and its
subsidiary legislation, specifically under the Health Products (Cell, Tissue and Gene
Therapy Products) Regulations 2021.2 Materials used in gene therapy such as viral or non-
viral vectors with genetic material, as well as clinical research materials used in non-
heritable gene editing, are classified as Class 2 CTGTP. Class 2 CTGTP comprises gene
modified cells, cells grown on scaffold, culture expanded cells, vectors with therapeutic
gene and xeno-based products. The conduct of clinical trials and use of clinical research
1
Ministry of Health. Licence Conditions for All Acute Hospital Service, Outpatient Dental Service and Outpatient
Medical Service Licensees Administering or Intending to Administer Cell, Tissue and Gene Therapy Products
Manufactured In-House by Healthcare Institutions. Healthcare Services Act 2020.
www.moh.gov.sg/docs/librariesprovider5/licensing-terms-and-conditions/lc-for-
ctgtp_260623.pdf?sfvrsn=e87f03b0_0. Retrieved on 8 February 2024.
2
Health Products Act 2007, Health Products (Cell, Tissue and Gene Therapy Products) Regulations 2021.
https://sso.agc.gov.sg/SL/HPA2007-S104-2021. Retrieved on 25 August 2023.
22
materials classified as Class 2 CTGTP are also regulated under the Health Products (Clinical
Trials) Regulations 2016.3
c. Healthcare Services Act 2020 (HCSA 2020)

2.5 The Licence Conditions for all Acute Hospital Service, Outpatient Dental Service and
Outpatient Medical Service Licensees Administering or Intending to Administer Cell,
Tissue and Gene Therapy Products Manufactured In-House by Healthcare Institutions
imposed under the Healthcare Services Act 2020 states that the use of in-house
manufactured CTGTPs 4 (including human cells or tissues, animal cells or tissues, and
genetically modified DNA/RNA carrying a therapeutic gene) for innovative salvage therapy
must be reviewed by (i) the healthcare institutions’ tumour board or specialty board for that
particular disease/condition, or at least two medical practitioners qualified to confirm the
patient’s need for the innovative salvage therapy due to the ineffectiveness or unsuitability
of current conventional therapy and who are independent of the patient’s treatment team;
and (ii) a CEC.1 However, mainstream clinical applications of non-heritable gene editing
are not approved for use in Singapore and there are no ongoing clinical trials on non-
heritable gene editing in Singapore.
ii. Heritable Gene Editing for Clinical Applications and Gene Editing in Embryos or
Germline Cells for Research
2.6 Heritable gene editing for clinical applications is not approved by the Ministry of Health
(MOH) in Singapore. This is because currently there is insufficient evidence to demonstrate
the safety of this novel technology. Research applications of gene editing in embryos or
germline cells, are strictly regulated in Singapore under the Human Biomedical Research
Act 2015,5 which falls under purview of the MOH in Singapore. Specific research projects
involving embryonic development, which require approval from government authorities,
are required to adhere to the requirements set out under the Human Biomedical Research
Act 2015. The BAC’s ‘Ethics Guidelines for Human Biomedical Research (2021 revised
edition)’ emphasises that written approvals from government authorities such as MOH are
required if the research involves human eggs and embryos.6
a. Human Cloning and Other Prohibited Practices Act 2004
2.7 In Singapore, the Human Cloning and Other Prohibited Practices Act 2004 stipulates that
placing of prohibited embryo in the body of a woman is prohibited.7 Prohibited embryo
3
Health Products Act 2007, Health Products (Clinical Trials) Regulations 2016.
https://sso.agc.gov.sg/SL/HPA2007-S331-2016. Retrieved on 28 August 2023.
4
In-House Manufactured CTGTPs refers to the non-commercial production of CTGTPs by a healthcare institution,
whether for use by patients of the healthcare institutions or to be distributed for use by patients in another
healthcare institution. It also includes the healthcare institution outsourcing this activity to a third-party
commercial entity to manufacture and re-supply the CTGTP back to the healthcare institution for use by their own
patients only.
5
Human Biomedical Research Act 2015, 2020 Rev Ed. Part 5: Regulation of Human Biomedical Research.
https://sso.agc.gov.sg/Act/HBRA2015. Retrieved on 28 August 2023.
6
Ethics guidelines for human biomedical research (2021 revised edition) (2021). Bioethics Advisory Committee.
https://www.bioethics-singapore.gov.sg/publications/reports/bac-ethics-guidelines-2021. Retrieved on 25 August
2023.
7
Human Cloning and Other Prohibited Practices Act 2004. Part III, Division 2, Section 11: Other prohibited
practices. https://sso.agc.gov.sg/Acts-Supp/35-2004/Published?DocDate=20040927&Provlds=pr13-
sso.agc.gov.sg/Act/HCOPPA2004?ViewType=Within&Phrase=14%20days. Retrieved on 28 August 2023.
23
includes any human embryo that has been developing outside the body of a woman for a
period of more than 14 days, excluding any period when the development is suspended, or
any embryo that is deliberately removed from the body of a woman with the intention of
obtaining a viable human embryo.7 The Act also strictly regulates the creation and
development of human embryos for research purposes in Singapore, and stipulates that a
person must not develop any human embryo, that is created by a process other than the
fertilisation of a human egg by human sperm, outside the body of a woman for a period of
more than 14 days.8 The duration of embryonic development excludes any period for which
the development of the embryo is suspended.8
b. Healthcare Services (Assisted Reproduction Service) Regulations 2023
2.8 Separately, the Healthcare Services (Assisted Reproduction Service) Regulations 2023
under the HCSA 2020 sets out that assisted reproduction procedure involves (a) the
collection of oocytes from a woman, other than by way of surgical excision of the woman’s
ovarian tissue; (b) the fertilisation of an oocyte for the subsequent distribution of the
embryo; (c) the transfer of any oocyte or embryo into the body of a woman; and (d) any
removal of cells from an embryo for the purpose of testing the embryo. 9 Under the HCSA
2020, an embryo is defined as any live embryo that has a human genome or an altered human
genome and that has been developing for less than 14 days since (a) its fertilisation; (b) the
appearance of two pro-nuclei; or (c) the initiation of its development by other means.10
When point (c) of the assisted reproduction procedure mentioned above is read together
with the definition of an embryo under HCSA 2020, it can be interpreted that the Healthcare
Services (Assisted Reproduction Service) Regulations 2023 do not prohibit heritable gene
editing for infertility in Singapore.
c. Human Biomedical Research (Restricted Research) Regulations 2017
2.9 The Human Biomedical Research (Restricted Research) Regulations 2017 requires that every
research institution and researcher in Singapore conducting restricted research 11 must
ensure that the research carried out does not involve a human embryo that is more than 14
days old from the time of creation, excluding any period when the development of the
embryo is suspended.12 The Regulations also require that the research institution and the
researcher ensure that only surplus embryos created in assisted reproduction treatment and
8
Human Cloning and Other Prohibited Practices Act 2004. Part III, Division 2, Sections 7 and 8: Other prohibited
practices. https://sso.agc.gov.sg/Act-Rev/HCOPPA2004/Published?DocDate=20050731&Provlds=pr7-,pr8-
https://sso.agc.gov.sg/Act/HCOPPA2004?ViewType=Within&Phrase=14%20days. Retrieved on 28 August
2023.
9
Ministry of Health. Healthcare Services (Assisted Reproduction Service) Regulations 2023. Healthcare Services
Act 2020. Part 1: Definitions. https://sso.agc.gov.sg/SL/HSA2020-S429-2023?DocDate=20230623. Retrieved on
8 February 2024.
10
Ministry of Health. Healthcare Services Act 2020. First Schedule: Licensable Healthcare Services.
https://sso.agc.gov.sg/Act/HSA2020?=&Provlds=Sc1-. Retrieved on 15 February 2024.
11
‘Restricted research’ refers to any restricted human biomedical research as set out in the Fourth Schedule of the
Human Biomedical Research Act 2015, including human biomedical research involving human egg or human
embryos.
12
Human Biomedical Research Act 2015 (Act 29 of 2015). S 622, Human Biomedical Research (Restricted
Research) Regulations 2017. Part 3, Section 10. Research involving oocytes and embryos.
https://sso.agc.gov.sg/SL/HBRA2015-S622-
2017/Historical/20171101?DocDate=20230621&ValidDate=20230501&Provlds=pr10-#pr10-. Retrieved on 28
August 2023.
24
embryos that are no longer required for therapeutic purposes may be used for research.
While the Regulations do not expressly prohibit research on heritable gene editing, specific
research projects involving embryonic development, would require approval from the
relevant government authorities, in addition to approval from the relevant IRBs.
II. Overseas Legislation for HNGE
i. Non-Heritable Gene Editing (for research and clinical applications)
2.10 Countries such as Australia, Germany, South Korea, New Zealand, the United States of
America (US), and the United Kingdom (UK) currently do not regulate non-heritable gene
editing for research. As such, non-heritable gene editing for research is allowed in these
countries. However, non-heritable gene editing for clinical applications are regulated by the
US and Europe.
The US
2.11 In the US, human gene editing falls under the purview of the Food and Drug Administration
(FDA) and the National Institute of Health (NIH). 13 Gene therapy products that seek to
modify or manipulate genetic expression to alter biological properties of living cells for
treatment purposes are regulated by the Center for Biologics Evaluation and Research
(CBER).14 Most products used in clinical applications of non-heritable gene editing, such
as viral or non-viral vectors, are regarded as biologic drugs and are regulated with gene
therapy products. While clinical applications of non-heritable gene editing are not
prohibited, they are required to be reviewed by the FDA pursuant to its authority under the
Federal Food, Drug, and Cosmetic Act (Public Law 75-717) and the Public Health Service
Act (Public Law 78-410).15 The US NIH Somatic Cell Genome Editing (SCGE) Consortium
was set up with the aim to accelerate the development of safer and more effective methods
for non-heritable gene editing in patients.16 This is because gene editing technologies have
been recognised for their potential to develop therapies for common and rare diseases caused
by genetic disorders. Therefore, improving the safety and efficacy of techniques employed
in non-heritable gene editing would provide greater therapeutic options for patients.
Europe
2.12 In Europe, non-heritable gene editing, along with gene therapy and tissue engineered
products, are classified as advanced therapy medicinal products (ATMPs) and are regulated
13
Liu, S. (2020) Legal reflections on the case of genome-edited babies - global health research and
policy, BioMed Central. https://ghrp.biomedcentral.com/articles/10.1186/s41256-020-00153-4. Retrieved on 25
August 2023.
14
Center for Biologics Evaluation and Research (n.d) Cellular & Gene Therapy Products, U.S. Food and Drug
Administration. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products. Retrieved on 25
August 2023.
15
National Academies of Sciences, Engineering, and Medicine; National Academy of Medicine; National
Academy of Sciences; Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations.
(2017). Human Genome Editing: Science, Ethics, and
Governance. https://www.ncbi.nlm.nih.gov/books/NBK447266/. Retrieved on 25 August 2023.
16
National Institutes of Health (2023). Somatic cell genome editing https://www.commonfund.nih.gov/editing.
25
by the European Medicines Agency (EMA). 17 Specifically, the European Union’s
Regulation (EC) No 1394/2007 provides the overall framework for ATMP regulation.18
This also includes materials used in clinical trials for non-heritable gene editing, which is
regulated by the Directive 2001/83/EC.19 ATMPs require licensing of clinical trials by the
Medicines and Healthcare Products Regulatory Agency, and market authorisation from the
EMA. The regulatory framework for AMTPs is designed to facilitate distribution of these
medicines within the European Union, while maintaining the highest level of protection for
the health and interest of patients.
ii. Heritable Gene Editing for Clinical Applications and Gene Editing in Embryos or
Germline Cells for Research20
2.13 Countries such as Australia, Germany, Israel, South Korea, New Zealand, and the US
prohibit heritable gene editing for clinical applications. Gene editing in embryos or germline
cells for research is allowed in Australia, South Korea, and New Zealand. The US, however,
prohibits federal funding for research carried out involving gene editing in germline cells.
Australia
2.14 In Australia, the use of human embryos in research is regulated under the Prohibition of
Human Cloning for Reproduction Act.21 The Act aims to address ethical concerns on the
scientific developments in relation to human reproduction and utilisation of human embryos
by prohibiting certain practices. Practices that are completely prohibited under the Act
include heritable alterations to genome. 22 A person therefore commits an offence if the
person alters the gene of a human cell in such a way that the alteration is heritable, or
intended to be inherited, by descendants of the human whose cell was altered. The Act also
17
European Medicines Agency (2023). Advanced therapy medicinal products: Overview, European Medicines
Agency. https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-
overview. Retrieved on 28 August 2023.
18
Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on
advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (no
date) EUR. https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=celex%3A32007R1394. Retrieved on 28
August 2023.
19
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community
code relating to medicinal products for human use (no date) EUR. https://eur-lex.europa.eu/legal-
content/EN/TXT/?qid=1410944582971&uri=CELEX%3A02001L0083-20121116. Retrieved on 28 August 2023.
20
Most of the legislation on heritable genome editing for clinical applications and genome editing in embryos or
germline cells for research include the mention of ’14-day rule’. While the ‘14-day rule’ is an international ethical
standard that limits laboratory studies in human embryos and requires scientists and researchers to destroy human
embryos grown in lab before they reach 14 days, some researchers and scientists favour revising the rule to further
study the embryonic developmental process, which happens between 14 and 28 days. Extending the ‘14-day rule’
might allow researchers to adopt simple treatment options (i.e., apart from surgical interventions) to reduce the
amount of pain the future child goes through due to congenital abnormalities that develop during this period
(quoted by British scientist, Robin Lovell-Badge, who is a stem cell expert at London’s Crick Institute). However,
some ethicists argue that such extension may cross a moral boundary and it is also unclear how such a change
would advance research. [Reference: See New guidelines suggest lifting ‘14-day rule’ on growing human embryos
in the lab (2021) NBCNews.com. https://www.nbcnews.com/health/health-news/new-guidelines-suggest-lifting-
14-day-rule-growing-human-embryos-n1268628]
21
Prohibition of Human Cloning for Reproduction Act 2002.
https://www.legislation.gov.au/Details/C2017C00306. Retrieved on 28 August 2023.
22
Prohibition of Human Cloning for Reproduction Act 2002. Section 15: Offence: heritable alterations to genome.
https://www.austlii.edu.au/au//legis/cth/consol_act/pohcfra2002465/s15.html. Retrieved on 28 August 2023.
26
prohibits developing a human embryo intentionally outside the body of a woman for a period
of more than 14 days, excluding any period when development is halted.
China
2.15 In China, any individual who, without obtaining the qualification for practising medicine,
unlawfully practises medicine shall be sentenced to a fixed-term imprisonment of not more
than three years, criminal detention, or public surveillance, and with or only fine if the
circumstances are serious. This is enshrined within Article 336 of the Criminal Law of the
People’s Republic of China and applies to human genome editing for clinical applications
or on germline cells.23 He Jiankui was charged and convicted under this Article for carrying
out gene editing on human embryos which were implanted into a woman and later born as
twin girls. The Chinese Civil Code, issued in May 2020, states that medical and scientific
research activities concerning human genes and embryos, among others, shall be performed
according to laws and administrative regulations and relevant provisions outlined by the
state without endangering human health, violating moral principles, or damaging public
interest. According to this, anyone who engage in relevant scientific research and medical
activities that contravene ethics and morality in China will be considered to have violated
personal rights and can be subject to civil liabilities.24
Germany
2.16 In Germany, the editing of germline cells is regulated under the Embryo Protection Act.25
Section 5 on artificial alteration of human germline cells under the Act states that anyone
who artificially alters the genetic information of a human germline cell will be punished
with imprisonment of up to five years or a fine. This does not apply to the artificial alteration
of the genetic information of a germ cell situated outside the body where the altered germ
cell is not used for fertilisation. The Act also states that anyone who uses a human germ cell
with artificially modified genetic information for fertilisation will be similarly punished.
Israel
2.17 In Israel, the use of reproductive cells that have undergone a permanent intentional genetic
modification (germline gene therapy) to cause the creation of a person is prohibited under
the Prohibition of Genetic Intervention (Human Cloning and Genetic Manipulation of
Reproductive Cells) Law.26
South Korea
23
Normille, D. (2023). In wake of gene-edited baby scandal, China sets new ethics rules for human studies.
https://www.science.org/content/article/wake-gene-edited-baby-scandal-china-sets-new-ethics-rules-human-
studies. Retrieved on 28 August 2023.
24
Yaojin, P.; Jianwei, Lv.; et. al. (2022). Responsible governance of human germline genome editing in China.
Biology of Reproduction; 101(1); pp 261-268. doi: 10.1093/biolre/ioac114
25
Federal Law Gazette (1990). Act for the protection of Embryos (The Embryo Protection Act).
https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/Gesetze_und_Verordnungen/G
uV/E/ESchG_EN_Fassung_Stand_10Dez2014_01.pdf. Retrieved on 28 August 2023.
26
Ornit (2004). Prohibition of Genetic Intervention (Human Cloning and Genetic Manipulation of Reproductive
Cells) Law, 5759-1999, The Hinxton Group: An International Consortium on Stem Cells, Ethics & Law.
http://www.hinxtongroup.org/docs/israel.html. Retrieved on 28 August 2023.
27
2.18 In South Korea, the Bioethics and Safety Act only permits gene therapy research for a
hereditary disease, Acquired Immune Deficiency Syndrome (AIDS), any other disease that
threatens one's life or causes a severe disability, as well as situations where there is no
applicable therapy at present or the effect of gene therapy is expected to be significantly
better than other therapies.27 This research should only be conducted before the primitive
streak of the embryo appears during embryonic development.28
New Zealand
2.19 In New Zealand, the Human Assisted Reproductive Technology Act prohibits the
implantation of a genetically modified gamete, human embryo, or hybrid embryo into a
human.29 The Act also prohibits research on non-viable embryos beyond 14 days.30
The US
2.20 The US’s ‘National Institutes of Health (NIH) Regulation’ states that NIH funds may not
be used for the creation of a human embryo or embryos for research purposes, and for
research in which a human embryo or embryos are destroyed, discarded, or knowingly
subjected to risk of injury or death greater than that allowed for research on foetuses in utero
under 45 CFR 46.204(b) and subsection 498(b) of the Public Health Service (PHS) Act (42
U.S.C. 289g(b)). NIH will not fund any use of gene-editing technologies in human embryos
for clinical application.31
III. Comparison Between Local and Overseas Legislation for HNGE
a. Non-Heritable Gene Editing (for Research and Clinical Applications)

2.21 Similar to Singapore, the countries of Australia, Germany, South Korea, New Zealand, the
US, and the UK do not have legislation explicitly prohibiting the use of non-heritable gene
editing in research.
2.22 The US and Europe generally regulate products of non-heritable gene editing as gene
therapies to be conducted under clinical trials, which is similar to the practice in Singapore.
However, in Singapore, in-house CTGTPs may be used for medical treatment if approved
by CECs.
b. Clinical Applications and Gene Editing in Embryos or Germline Cells for Research
27
Bioethics and Safety Act No. 12844 (2014). Article 47: Gene Therapies.
https://elaw.klri.re.kr/eng_mobile/viewer.do?hseq=33442&type=part&key=36. Retrieved on 28 August 2023.
28
Bioethics and Safety Act No. 12844 (2014). Article 29: Residual Embryos Research.
https://elaw.klri.re.kr/eng_mobile/viewer.do?hseq=33442&type=part&key=36. Retrieved on 29 January 2024.
29
Parliamentary Counsel Office. Human Assisted Reproductive Technology Act 2004 - New Zealand legislation.
Schedule 1: Prohibited actions. https://legislation.govt.nz/act/public/2004/0092/latest/whole.html#DLM319832.
30
Parliamentary Counsel Office. Human Assisted Reproductive Technology Act 2004 - New Zealand legislation.
Part 2: Prohibited and regulated activities.
https://legislation.govt.nz/act/public/2004/0092/latest/whole.html#DLM319311 . Retrieved on 29 January 2024.
31
Francis, S. (2015). Statement on NIH funding of research using gene-editing technologies in human embryos
National Institutes of Health. https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-
funding-research-using-gene-editing-technologies-human-embryos. Retrieved on 28 August 2023.
28
2.23 In Australia, Germany, Israel, South Korea, New Zealand, and the US, there is legislation
in place to prohibit heritable gene editing for clinical applications, which are similar to the
Human Cloning and Other Prohibited Practices Act 2004 in Singapore. At the same time,
Australia, New Zealand, Germany, and South Korea also allow gene editing in embryos or
germline cells for research purposes, similar to the position under Singapore’s Human
Biomedical Research Act 2015. Singapore allows research on embryos from the time of
creation to 14 days or appearance of the primitive streak, whichever is earlier. In contrast,
Australian and New Zealand legislation only references the ‘14-day rule’, whereas South
Korean legislation mentions only the appearance of the primitive streak. However, German
legislation does not reference either the ‘14-day rule’ or the appearance of the primitive
streak.
2.24 South Korea’s laws specify that gene therapy research should only be conducted for
hereditary diseases or diseases that threaten one’s life or cause a severe disability, and for
diseases that have no applicable therapy at present. In contrast, Singapore’s Human
Biomedical Research (Restricted Research) Regulations 2017 does not specify the scope of
gene editing in embryos or germline cells for research purposes, as is the case for the
corresponding Australian and New Zealand legislation. Separately, gene editing in embryos
or germline cells for research purposes is prohibited with the use of federal funding in the
US, but is not otherwise prohibited.32 However, unlike Singapore, the legislation in the US
do not specify the need to conduct such research on embryos before 14 days or the
appearance of the primitive streak.
IV. Overview of Guidelines for HNGE
2.25 While there are no specific guidelines on HNGE in Singapore, the BAC had previously
recommended in its report on ‘Genetic Testing and Genetic Research (2005)’ that the
clinical practice of germline genetic modification should not be allowed. 33 The BAC has
also recommended in its report on ‘Ethics Guidelines for Human Biomedical Research
(2021 Revised)’ that research involving human germline modification for purposes other
than the prevention or treatment of serious genetic conditions should not be allowed, and
reiterated that the clinical practice of germline modification should be prohibited until there
is adequate evidence from research that such clinical procedures are safe and effective.34
2.26 The World Health Organization (WHO) developed recommendations on the governance
and oversight of human gene editing in nine discrete areas, including human genome editing
registries and illegal, unregistered, unethical or unsafe research. 35 The International
32
Stein, R. (2019) New U.S. experiments aim to create gene-edited human embryos, NPR.
https://www.npr.org/sections/health-shots/2019/02/01/689623550/new-u-s-experiments-aim-to-create-gene-
edited-human-
embryos#:~:text=The%20U.S.%20government%20prohibits%20the,embryos%20to%20create%20a%20pregna
ncy. Retrieved on 28 August 2023.
33
The Bioethics Advisory Committee, Singapore (2005). Genetic Testing and Genetic Research Report.
https://www.bioethics-singapore.gov.sg/files/publications/reports/genetic-testing-and-genetic-research-full-
report.pdf. Retrieved on 28 August 2023.
34
Ethics guidelines for human biomedical research (2021 revised edition) (2021). Bioethics Advisory Committee.
Annexe A, Section 5.33. https://www.bioethics-singapore.gov.sg/publications/reports/bac-ethics-guidelines-2021.
Retrieved on 31 January 2024.
35
WHO issues new recommendations on human genome editing for the Advancement of Public Health (2021).
World Health Organization. https://www.who.int/news/item/12-07-2021-who-issues-new-recommendations-on-
human-genome-editing-for-the-advancement-of-public-health. Retrieved on 28 August 2023.
29
Commission on the Clinical Use of Human Germline Genome Editing recommends that a
country should only allow heritable gene editing for clinical applications, if it meets the
criteria stated in paragraph 2.32.36
2.27 The International Society for Stem Cell Research (ISSCR) recommends against the use of
heritable gene editing for therapeutic purposes, but support the use of gene editing in
embryos or germline cells for research purposes. Ethics bodies such as the German Ethics
Council and the Spanish Bioethics Committee on Genome Editing in Humans have also
recommended against the use of heritable gene editing for clinical applications. Similarly,
Japan has developed guidelines that recommend against the use of heritable gene editing for
clinical applications.
V. HNGE Guidelines Which Explicitly Recommend Against Heritable Gene Editing
a. The WHO Expert Advisory Committee on Developing Global Standards for

Governance and Oversight of Human Genome Editing
2.28 In 2021, the WHO Expert Advisory Committee on Developing Global Standards for
Governance and Oversight of Human Genome Editing developed new recommendations
and published two reports (framework for governance; recommendations) aiming to help
establish human (both non-heritable and heritable) gene editing as a tool for public health
across the world.37 The report on framework for governance serves to provide guidance to
different groups of stakeholders to strengthen governance of the technology at the
institutional, national, regional, and global levels. The Committee’s report on the
recommendations are for both clinical and research applications of gene editing, and include
advocacy for changes to policy and practice to support the reporting of possible illegal,
unregistered, unethical, or unsafe non-heritable gene editing, heritable gene editing, and
gene editing in embryos or germline cells for research purposes. Countries are encouraged
to utilise the tools for governance set out in the WHO report on framework for governance
and collaborate with the WHO to ensure that the recommendations of the Committee are
effectively implemented.
b. The International Society for Stem Cell Research (ISSCR)
2.29 The International Society for Stem Cell Research (ISSCR) Guidelines (2021) recommend
the use of gene editing on germline cells for research purposes only after review and
approval through a specialised scientific and ethics review process.38 The ISSCR Guidelines
also recommend that a specialised scientific and ethical oversight process may be used to
assess whether the scientific objectives require the time for the embryo to be developed in
culture beyond 14 days. The guidelines also recommend that research involving human
embryos in which their nuclear genome have undergone modification are not allowed to be
36
National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human
Genome Editing. Washington, DC: The National Academies Press. https://doi.org/10.17226/25665. Retrieved on
28 August 2023.
37
Human genome editing: Recommendations (2021). World Health Organization.
https://www.who.int/publications/i/item/9789240030381. Retrieved on 28 August 2023.
38
International Society for Stem Cell Research (ISSCR) Guidelines (2021). https://www.isscr.org/docs/default-
source/all-isscr-guidelines/2021-guidelines/isscr-guidelines-for-stem-cell-research-and-clinical-translation-
2021.pdf?sfvrsn=ced254b1_4. Retrieved on 28 August 2023.
30
transferred into or gestated in a human uterus, as these approaches are currently unsafe or
raise unresolved ethical issues.
c. German Ethics Council: Intervening in the Human Germline (Opinion - Executive

Summary & Recommendations) (2019)
2.30 In Germany, the German Ethics Council published a report ‘Intervening in the Human
Germline’ calling for an international moratorium on heritable gene editing for medical
purposes in humans. 39 The report serves to encourage discussion and evaluation on the
possible goals of germline interventions in humans, determine the cases and conditions for
which germline interventions may be allowable in the future, prevent premature applications
of the same and to allow time for careful basic and preclinical research to determine the
safety and efficacy of heritable gene editing for clinical applications.
d. Japan’s Guidelines for Research Using Gene-altering Technologies on Human

Fertilised Embryos (2019)
2.31 In Japan, the Guidelines for Research Using Gene-altering Technologies on Human
Fertilised Embryos support the gene editing of human embryos for research aimed at
understanding disease development to treat genetic diseases. The Guidelines, however,
recommend against germline gene editing for reproductive purposes and clinical testing.40
VI. HNGE Guidelines that Recommend Heritable Gene Editing be Allowed on

Conditions
a. The International Commission on the Clinical Use of Human Germline Genome

Editing (2020)
2.32 The International Commission on the Clinical Use of Human Germline Genome Editing
aims to provide a framework for scientists, clinicians, and regulatory authorities to consider
when assessing potential clinical applications of heritable gene editing, if heritable gene
editing applications were to be socially acceptable in the future.36 It recommends that the
use of heritable gene editing for treatment of diseases and infertility should be permitted
only under the following conditions:
(i) serious monogenic diseases that cause severe morbidity or premature death;
(ii) changing a pathogenic genetic variant known to be responsible for the serious
monogenic disease to a sequence that is common in the relevant population and that
is known not to be disease-causing;
39
German Ethics Council (2018) Germline intervention in the human embryo.
https://www.ethikrat.org/fileadmin/Publikationen/Ad-hoc-Empfehlungen/englisch/recommendation-germline-
intervention-in-the-human-embryo.pdf. Retrieved on 28 August 2023.
40
Public Notice of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Ministry of
Health, Labor and Welfare (MHLW) (2019). Guidelines for research using gene-altering technologies on human
fertilized embryos are established as follows, and shall come into force as from the date of promulgation.
https://www.lifescience.mext.go.jp/files/pdf/Overview_Human_embryo_geneome-editing_guideline2019En.pdf
Retrieved on 8 February 2024.
31
(iii) ensuring that no embryos without the disease-causing genotype will be subjected to
the process of genome editing and transfer, and no individuals resulting from edited
embryos are exposed to risks of HNGE without any potential benefit; and
(iv) situations in which prospective parents have no option for having a genetically
related child that does not have the serious monogenic disease, because none of
their embryos would be genetically unaffected in the absence of genome editing; or
have extremely poor options, because the expected proportion of unaffected
embryos would be unusually low, which the Commission defines as 25 percent or
less, and have attempted at least one cycle of preimplantation genetic testing
without success.
b. The World Medical Association’s Statement on Human Genome Editing

2.33 The World Medical Association issued a statement on human gene editing in 2020
recommending that human gene editing should be implemented according to appropriate
evidence that is collected via well-conducted and ethically approved research studies.41 The
statement also states that gene editing on germline cells for research purposes should be
allowed only within a separate ethical and legal framework, distinct from any ethical and
legal frameworks applied to non-heritable gene editing. The World Medical Association
further recommends that governments should support the continued development of an
international consensus, grounded in science and ethics, to determine allowable therapeutic
applications of germline gene editing.
2.34 Legislation and guidelines play an important role in navigating the ethical, legal and social
implications surrounding gene editing. It is important for researchers and research
institutions to adhere to these legislation and guidelines to ensure ethical and safe utilisation
of gene editing technologies. These frameworks provide the necessary safeguards against
potential risks from applications of gene editing technologies and protect human health and
societal values. This also ensures benefits of gene editing are realised in a manner that
respects the autonomy and rights of all individuals and communities.
41
World Medical Association (2020). WMA statement on human genome editing. https://www.wma.net/policies-
post/wma-statement-on-human-genome-editing/. Retrieved on 15 March 2024.
32
CHAPTER 3: GENERAL ETHICAL PRINCIPLES IN HNGE
General Ethical Principles
3.1 In its deliberations on the use of HNGE in biomedical research and clinical applications, the
BAC stays guided by substantive1 and governance principles. Substantive principles include
considerations on ‘Respect for persons’, ‘Solidarity’, ‘Justice’, ‘Proportionality’ and
‘Sustainability’, which are discussed in greater detail as follows:
a. Respect for persons
3.2 Respect for persons directs us to treat individuals as beings with value in themselves or
autonomy over their own life and, accordingly, to respect their right to make their own
decisions without being coerced, misled, or kept in ignorance. The welfare and interests of
individuals are to be protected, especially when their autonomy is impaired or lacking. This
principle underlies the importance of obtaining informed consent from potential research
participants or those who are making decisions on behalf of them or entities in research,
protection of their privacy and confidentially disclosed information, and preventing or
minimising harm to them.
3.3 In the context of HNGE, the principle of respect for persons refers to the autonomy of
individuals making decisions related to biomedical research involving gene editing or its
clinical applications. The autonomy of a person may be compromised if they are not fully
informed of the possible benefits, risks, and repercussions following research and clinical
applications of gene editing technologies. Individuals have the autonomy and right to decide
whether to undergo non-heritable gene editing, and the autonomous right to engage in
germline human gene editing for their offspring. Gene editing in embryos or germline cells
for research, heritable gene editing for treatment of diseases, conferring resistance,
enhancement of traits, and for infertility, if permitted in the future, may indirectly
compromise on the rights, autonomy and physical integrity of the child born as a
consequence of the intervention. While gene editing does not violate autonomy and rights
of modified embryos or germline cells since they have no autonomy per se that can be
violated, some argue that it infringes the autonomy and rights of the child who is
consequently born to an open future, where gene editing limits the range of set life-options,2
since he is unable to provide consent prior to being genetically modified.
b. Solidarity
3.4 The BAC takes the position that some measure of mutual obligation exists between the
individual and society such that in specified circumstances, individual interests ought to be
subordinated to achieve or promote the public good. The principle of solidarity reflects the
moral obligations of individuals, like participants, researchers, and research institutions, to
share the costs associated with research design and execution, including potential risks, in
1
Bioethics Advisory Committee. (2022). Ethical Principles. Bioethics Advisory Committee.
https://www.bioethics-singapore.gov.sg/who-we-are/ethical-principles/. Retrieved on 28 August 2023.
2
Mintz, R.L., Loike, J.D., Fischbach, R.L. (2019). Will CRISPR Germline Engineering Close the Door to an
Open Future? Science and Engineering Ethics, 25(5), pp. 1409-1423. https://philpapers.org/rec/MINWCG.
Retrieved on 26 April 2024.
33
return for the common good. In the context of biomedical research, acceptance of agreed
social benefits is typically considered as a public good. This supports an in-principle
willingness to consider participation in research that yields the accepted benefits. There is
also a need to balance the interests of the public or society with the rights and interests of
individual participants such that individual interests are not unnecessarily sacrificed but also
advanced as part of the public good. This would help resolve any incompatible and
irreconcilable perspectives on the good or right thing to do.
3.5 Solidarity reflects the importance of general altruism and other pro-social motives as a basis
for participation in biomedical research. For instance, research in human gene editing may
harness benefits for the society by enabling faster and accurate diagnosis of diseases or
conditions in patients, introducing more targeted treatments, and allowing early prevention
of the occurrence of genetic disorders. While biomedical research is important in realising
long-term benefits from the applications of gene editing, it is also crucial to note that misuse
and abuse of such technologies for inappropriate purposes or to effect personal trait
preferences could lead to the neglect or failure to discharge obligations towards certain
subgroups, such as those suffering from rare disease.
c. Justice
3.6 The principle of justice encompasses the general principles of fairness and equality for all
individuals, which implies that access to the benefits of biomedical research, and the burden
of supporting it, should be equitably shared in society. In the event that research yields an
immediate benefit that could apply to participants in the research, the principle of justice
would dictate that the benefits are shared with them fairly as a way of reciprocating their
contribution to the research. The principle of justice also implies that researchers and their
institutions shoulder some responsibility for the welfare of participants in the event of
adverse outcomes arising directly from their participation in the research.
3.7 In the context of research and clinical applications of HNGE, justice requires that gene
editing technologies and therapies are accessible to the public according to a plausible
theory of justice. However, the technologies involved may raise concerns on ensuring fair
access to therapies due to the high cost incurred. As such, treatments involving the use of
gene editing technologies may not be widely and readily accessible to the whole population,
particularly in lower socioeconomic status groups, 3 which may lead to societal inequity
issues.
d. Proportionality
3.8 The principle of proportionality requires that the regulation of research should be
proportional to the degree of possible threats to autonomy, individual welfare, or the public
good. As such, interference with individuals’ decisions and/or actions should not exceed
what is needed to achieve necessary regulation to promote public interest. The principle also
implies that the risk in any acceptable programme of research, and the stringency of its
regulation, should not be disproportionate to any anticipated benefits.
3
Hildebrandt, C.C. and Marron, J.M. (2018) Justice in CRISPR/cas9 research and clinical applications. Journal
of Ethics | American Medical Association. https://journalofethics.ama-assn.org/article/justice-crisprcas9-
research-and-clinical-applications/2018-09. Retrieved on 28 August 2023.
34
3.9 When assessing the use of gene editing technologies in biomedical research or clinical
purposes, the potential benefits to individuals and the society brought about by the editing
of the human genome should outweigh the anticipated risks of such research and clinical
applications. The stringency of any regulation or governance framework developed for
research employing gene editing, including a de facto prohibition on specific research
activities, must be proportionate to the risks being mitigated.
e. Sustainability
3.10 The principle of sustainability is understood broadly to support arguments for the
conservation of nature and the minimisation of resource depletion for the good of the planet.
Therefore, research processes and outcomes should not unfairly jeopardise or prejudice the
welfare of future generations.
3.11 In the context of human gene editing in biomedical research or clinical purposes, while gene
editing technologies can bring about social benefits, research involving human embryos,
and heritable gene editing for treatment of diseases, conferring resistance, enhancement of
traits, or treatment for infertility, might harm the offspring and its future generation directly
or indirectly due to the risks of genetic mutation. Researchers and research institutions are
encouraged to allocate and expend research resources appropriately to support HNGE
research activities as long as they are not misused and remain, in alignment with the United
Nation (UN) Sustainable Development Goals4.
Other considerations: Beneficence and non-maleficence

While the principles of beneficence and non-maleficence are not listed explicitly among the BAC’s five
substantive principles mentioned above, these two principles are instantiated by some of the five
principles.
• Solidarity and beneficence: Beneficence preserves individual human welfare, which should be
taken into consideration when social benefits are weighed (i.e., principle of solidarity).
• Proportionality and beneficence: The benefits to individuals (i.e., beneficence) need to be
considered when risks and benefits are weighed (i.e., proportionality).
• Sustainability and non-maleficence: Both principles focus on minimising possible harm though
sustainability applies this to the future generations, and non-maleficence focuses on individual
welfare.
Governance Principles
3.12 In addition to the five substantive principles discussed above, the BAC has identified three
governance principles as being important in the context of HNGE in biomedical research
and clinical applications. These principles aim to guide researchers and institutions in
ensuring that an appropriate approach to govern gene editing for research purposes and
clinical interventions is adopted.
4
United Nations. (2015). 17 Sustainable Development Goals. THE 17 GOALS | Sustainable Development
(un.org). Retrieved on 19 January 2024.
35
I. Inclusivity
3.13 Biomedical research conducted and clinical care rendered should be representative of the
population diversity in Singapore and the benefits of such research and proper clinical care
should be globally accessible. The advancement of health equity through research is
promoted by community engagement and participatory research. Stakeholders may be
engaged through dialogues, public consultation, and consensus-building within the local
community.
3.14 In the context of HNGE, benefits of research and potential clinical applications of the
technology are considered a public good and need to be accessible to everyone. However,
the ethical implications of HNGE could exacerbate the divergent views of technology in
society, especially among groups with different social, cultural, and religious views. Hence,
there is a need to carefully consider the knowledge and perspectives on HNGE informed by
different social, cultural, and religious beliefs. And to also work closely with the different
groups of people to facilitate ‘community-engaged research’, where their opinions and
perspectives are considered during the conceptualisation of research plans.
3.15 Decision-makers should consider the views of all stakeholders and take them into account
where possible. Appropriate stakeholders such as patients, prospective parents, and the
public should be consulted and engaged to identify, prioritise and reach consensus on the
specific areas, topics, or questions that the research employing gene editing aims to address.
This engagement can help researchers understand the needs and concerns of its stakeholders.
Meaningful stakeholder engagement occurs when there is an opportunity to influence future
outcomes. In the context of human gene editing in biomedical research, this may include
input to research design, ethical oversight or overall governance of the research and the
research findings.
II. Transparency
3.16 Transparency relates closely to ethical responsibility and moral and legal liability for the
decisions and actions arising directly from research studies should be attributed to
researchers and their institutions. Research methods, analysis and data must be reported and
disseminated openly, clearly, comprehensively and in a timely manner. Transparency in
reporting of research helps to ensure that results are reproducible and reliable, and facilitates
proper interpretation and dissemination of findings by other researchers. Transparent
reporting mechanisms may also be set up to investigate concerns and possible unlawful
doings, as well as to provide support and protection for whistle-blowers. To allow
meaningful input from stakeholders such as the public into policy development with regard
to the use of HNGE 5 , policymakers have to institute policies, frameworks and
recommendations for research and clinical applications of technologies, including novel and
upcoming ones, in a transparent way to promote public confidence. Meaningful public input
with regard to the allowing or disallowing of HNGE technologies may need to be
5
National Academies of Sciences, Engineering, and Medicine; National Academy of Medicine; National
Academy of Sciences; Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations.
(2017) Oversight of Human Genome Editing and Overarching Principles for Governance. Human genome editing:
Science, ethics, and governance. Washington, District of Columbia: National Academies Press.
https://www.ncbi.nlm.nih.gov/books/NBK447266/. Retrieved on 28 August 2023.
36
incorporated into the policy-making process, where government decisions should be subject
to transparent social debate.
III. Responsible Stewardship of Science
3.17 The principle of responsible stewardship of science refers to the moral requirement to be
prudent about the resources and having oversight of all elements responsibly, including
planning, management, and decision-making in research activities in the pursuit of any
emerging field in biomedical research.6 Both evidence-informed basic and applied research
need to be pursued with appropriate caution given the uncertainty and risks involved.
Established ethical practices, ethical guidelines and legislations should be followed when
conducting research on humans, with particular attention to issues of integrity and conflict
of interest. Research priorities should also be set by considering the needs of the society and
in achieving maximum social and scientific benefits of research while minimising the
potential risks.
3.18 In the context of HNGE in biomedical research, responsible stewardship of science requires
that processes and outcomes of HNGE research be aligned with the values, needs, and
expectations of society, as identified through stakeholder engagement. This extends beyond
the dissemination of information and requires taking into consideration the views of all
stakeholders, as elaborated earlier under the principle of inclusivity.
3.19 In addition, there should be oversight mechanisms in place to ensure research activities are
conducted appropriately. For instance, an advisory group could be established within
research institutions to oversee the research priority setting process for gene editing
research. The group may comprise members from diverse background (e.g., research,
medical, administrative) to advise on the current policy and research considerations, assist
with the identification of stakeholders, and provide inputs in finalising the research
priorities. It is important for researchers and institutions to practise appropriate caution for
uncertainty and long-term risks when using gene editing technologies for both research and
clinical applications. There is also a need to ensure that there are clear and well-established
protocols and processes for oversight and review to ensure that research is conducted in an
ethical manner.
6
Daniel P. Sulmasy (2017). Ethical Principles, Process, and the Work of Bioethics Commissions. Goals and
Practice of Public Bioethics: Reflections on National Bioethics Commissions, special report, Hastings Center
Report 47, no. 3 (2017), S50-S53. https://doi.org/10.1002/hast.722.
37
CHAPTER 4: HNGE TECHNIQUES/TECHNOLOGIES AND THEIR
RELATIONSHIP WITH GENE AND CELL THERAPIES
Gene editing technologies widely used for research
4.1 Techniques and tools developed for HNGE have evolved since inception of the technology.
Nonetheless, the general steps involved in gene editing for research are similar1 and broadly
begin with targeting the area of deletion and subsequent insertion of genes within the
genome by introducing proteins or enzymes to cleave the DNA strands. The target DNA is
then removed before insertion of replacement DNA or modification/disruption of the gene.
The replacement DNA is typically used as the template to repair the break and generate a
healthy form of the gene. (See Fig. 4.1 for the schematic diagram)
Figure 4.1: Schematic diagram showing the general steps involved in gene editing2
Step 3a: Insertion

of replacement
Step 1: Area of deletion and Step 2: DNA3 Step 4: The replacement DNA
subsequent insertion is targeted Removal of is used as the template to repair
and proteins/ enzymes are target DNA the break.
introduced to cut the DNA
Step 3b:
strands. Modification or
disruption of
gene
Epigenetic modifications
4.2 Besides directed genetic alterations, epigenetic modifications can also be made to DNA to
regulate its expression by turning the genes on and off and influencing protein production
in cells. Unlike gene editing, such processes are reversible as they do not change the DNA
sequences on the genome (Fig. 4.2). As the focus of this report is on heritable genetic
changes resulting from human gene editing that causes changes in DNA sequence,
epigenetic modification and its technologies will not be discussed in detail, given that
epigenetic modification involves alterations of DNA accessibility and chromatin structure
instead of DNA sequence to regulate patterns of gene expression.43
1
National Human Genome Research Institute (2017). How Does Genome Editing Work?
https://www.genome.gov/about-genomics/policy-issues/Genome-Editing/How-genome-editing-works.
Retrieved on 7 September 2023.
2
As these are the general steps involved in gene editing, the specific details may vary for different types of gene
editing. E.g. base editing does not involve the complete removal of a nucleotide.
3
Replacement DNA is only required if the break is repaired via a pathway called ‘homology-directed repair
(HDR)’. Replacement DNA is not necessary if the break is repaired via another pathway called ‘non-homologous
end-joining (NHEJ)’. More will be discussed in later sections.
4
Diane, E., Rita, C., and Joseph, L. (2011). Epigenetic Modifications: Basic Mechanisms and Role in
Cardiovascular Disease. doi:10.1161/CIRCULATIONAHA.110.956839.
38
Figure 4.2: Schematic illustration of gene editing, epigenetic modification, and cell and
gene therapy
Different types of gene editing technologies
4.3 While there are many types of gene editing technologies, such as Restricted enzymes, Cas-
CLOVER,5 4 retrons,66 5 and meganucleases,7 6 the core technologies that are now most
commonly used by scientists and researchers to facilitate gene editing are ZFNs, CRISPR-
Cas987and TALENs (Fig. 4.3 and 4.4).
5
Madison, B.B. et al. (2022). CAS-clover is a novel high-fidelity nuclease for safe and robust generation of
TSCM-enriched allogeneic car-T cells, Molecular Therapy - Nucleic Acids, 29, pp. 979–995.
doi:10.1016/j.omtn.2022.06.003.
6
Zhao, B. et al. (2022). Bacterial retrons enable precise gene editing in human cells, The CRISPR Journal, 5(1),
pp. 31–39. doi:10.1089/crispr.2021.0065.
7
Silva, G. et al. (2011). Meganucleases and other tools for targeted Genome Engineering: Perspectives and
challenges for gene therapy, Current Gene Therapy, 11(1), pp. 11–27. doi:10.2174/156652311794520111.
8
This report focuses on the CRISPR-Cas9 complex as the conventional CRISPR complexes consist of the Cas9
enzyme. Cas3 and Cas12a are other examples of enzymes used in the CRISPR complexes.
39
Figure 4.3: Diagram of the different types of gene editing technologies in simple terms8
Gene editing technologies
ZFN CRISPR-Cas9 TALENs
Definition: ZFNs are synthetic proteins Definition: CRISPR-Cas9 is a DNA Definition: TALENs are artificial
used for gene targeting to introduce or gene editing tool that cuts DNA at restriction enzymes and can cut DNA
insertions or deletions at cut sites in the precise locations, allowing for its strands at any desired sequence.
genomes of living cells. accurate and targeted renewal or
replacement. Example of research studies that used
Example of research studies that used TALENs:
ZFN: New gene editing techniques using the • Researchers in UK demonstrated
• Gene editing clinical trial in the CRISPR-Cas9 system: the first-in-human use of TALEN
US used ZFN product • Base editing: Making precise gene-edited T-cells in two infants
GRm13Z40-2 for the treatment of changes in DNA without with refractory relapsed B-cell
stage III or IV malignant glioma causing double-strand breaks. acute lymphoblastic leukaemia,
patients in 2010.9 • Prime editing: Making and this therapeutic application of
targeted small insertions, TALEN-engineered cells
deletions, and base swapping in highlights the feasibility and
a precise way, without the need potency of gene-editing strategies
for donor DNA templates. It for the delivery of anti-tumor
uses a donor Ribonucleic Acid immunity.11
(RNA) template and a reverse
transcription mechanism.
Example of research studies that used

CRISPR-Cas9:
• A genome editing research in
the US in 2017 using CRISPR-
Cas 9 revealed a role for OCT4
in human embryogenesis.10
9
Hongyi, L. et al. (2019). Applications of genome editing technology in the targeted therapy of human diseases:
mechanisms, advances and prospects. doi: 10.1038/s41392-019-0089-y.
10
Norah, M. et al. (2017). Genome editing reveals a role for OCT4 in human embryogenesis. Nature, 550(7674):
pp 67-73. doi:10.10138/nature24033.
11
National Health Service, UK (2015). World first use of gene-edited immune cells to treat ‘incurable’ leukaemia.
https://www.gosh.nhs.uk/press-releases/world-first-use-gene-edited-immune-cells-treat-incurable-leukaemia/.
40
Figure 4.4: Diagram of the different types of gene editing technologies with more details9
Gene editing technologies
CRISPR-Cas9 TALENs
ZFN
Definition:
- CRISPR-Cas9 consists of a homing Definition:
Definition: device (the CRISPR part) that guides - TALENs are DNA-binding domains
- ZFNs are a class of synthetic DNA- molecular scissors (the Cas9 enzyme) to that can be engineered to cut specific
binding proteins that are used for a targeted section of DNA. sequences of DNA.
targeted genome editing by - The CRISPR-Cas9 system acts in a - TALENs are made by fusing a
generating double stranded breaks sequence-specific manner by recognising transcription activator-like (TAL)
(DSBs) on targeted DNA to create and cleaving foreign DNA. CRISPR- effector DNA-binding domain to a
an insertion or deletion (indel) for Cas13 is a related system that cleaves DNA cleavage domain.
disrupting the gene function. RNA.
- ZFNs use DNA binding domains Example of research studies that used
(also known as zinc fingers) that New gene editing techniques using the TALENs:
CRISPR-Cas9 system:
recognise ~ 3 bp sequences linked • Researchers in UK demonstrated the
• Base editing: Base editors such as
together to generate arrays which first-in-human use of TALEN gene-
cytidine base editors and adenine base
allow desired DNA sequences to be edited T-cells in two infants with
editors allow the introduction of point
targeted. mutations in the DNA without refractory relapsed B-cell acute
generating double stranded DNA lymphoblastic leukaemia, and this
Example of research studies that used therapeutic application of TALEN-
ZFN: breaks (as seen in the conventional
CRISPR-Cas9 system). There are two engineered cells highlights the
• A study conducted in the US used a
classes of base editors. Cytosine base feasibility and potency of gene-
human lymphoblast cell line derived
editors convert cytosine to thymine. editing strategies for the delivery of
from chronic myeloid leukaemia
Adenine base editors convert adenine anti-tumor immunity.11
(CML) patients, and a custom
to guanine. Base editing does not
designed ZFN to deliver site- require donor DNA templates.
specific double strand breaks to the • Prime editing: Prime editing uses the
telomeric portion of the mixed cell’s intrinsic DNA mismatch repair
lineage leukaemia (MLL) gene mechanism and enables targeted
breakpoint cluster region as well as editing without generating double-
to analyse chromosomal stranded DNA breaks and allows for
rearrangements associated with targeted insertions to be achieved
MLL leukaemogenesis via DSB without the need for donor DNA
error repair.12 templates. It uses a donor RNA
• Gene editing clinical trial in the US template and a reverse transcription
used ZFN product GRm13Z40-2 for mechanism.
the treatment of stage III or IV
Example of research studies that used
malignant glioma patients in 2010.9 CRISPR-Cas9:
• A genome editing research in the US in
2017 using CRISPR-Cas9 revealed a
role for OCT4 in human
embryogenesis.10
• Haematological disease clinical trial
conducted in China in 2019 applied
CRISPR/Cas9 to correct the
haemoglobin beta (HBB) gene in vitro
in patient-specific induced
haematopoietic stem cells (iHSCs), and
intravenously transfused the edited
cells back to the HBB-mutated β-
thalassemia subjects.13
12
Do, T. et al. (2012). A Zinc finger nuclease induced DNA double stranded breaks and rearrangements in MLL.
Mutat. Res. 740, pp 34 – 42. doi:10.1016/j.mrfmmm.2012.12.006.
13
Xie, Y. et al. (2019). CRISPR/Cas9 gene correction of HbH-CS thalassemia-induced pluripotent stem cells.
doi:10.1007/s00277-019-03763-2.
41
The relationship between gene editing, gene therapy, and cell therapy10 1112
4.4 Gene editing results in permanent alteration of the genetic material of a living organism by
inserting, replacing, or deleting a DNA sequence at a particular location in the genome.
Gene editing targets the genetic sequence of interest and introduces breaks or chemical
modifications to the DNA. In gene editing, breaks among DNA strands are repaired via one
of two pathways: homology-directed repair (HDR) and non-homologous end-joining
(NHEJ).14 HDR takes place when a replacement DNA is inserted and used as a template to
repair the break, while NHEJ repairs the break without the need for a replacement DNA to
act as a template. NHEJ is less accurate in carrying out the repair of Cas9-induced DNA
double strand breaks and it is difficult to control outcomes of NHEJ. Gene editing may be
carried out using gene editing tools such as ZFNs, CRISPR-Cas9 and TALENs.
4.5 Gene therapy refers to the treatment of a patient by altering the patient’s genetic
composition with exogenous DNA.15 This may involve using an extra-chromosomal DNA
that is not subsequently integrated into the subject’s genome, or the modification of the
genome via gene editing. Gene therapy is a technique employed to change an individual’s
genetic makeup with the intent to treat or cure genetic diseases and can work by:
i. replacing a disease-causing gene with a healthy copy of the gene;

ii. inactivating a disease-causing gene that is dysfunctional;
iii. introducing a new or modified gene into the body to help treat a disease; or
iv. correcting disease-causing mutations.
Gene therapy may be performed in vivo, in which the therapeutic gene is directly delivered
to cells inside the patient’s body, or ex vivo, in which the therapeutic gene is inserted into
cells outside the body before being introduced into the body. Ex vivo gene therapy is also
a form of cell therapy. Gene therapy is generally carried out using genetically modified
cell-based immunotherapies, viral vectors, gene editing, and non-viral vectors.
4.6 Cell therapy refers to the introduction of new cells into a patient’s body to grow, replace
or repair damaged tissue in order to treat a disease.16 The treatment regimen may employ
cells from the patients’ own body (autologous) or from a donor (allogenic). Cell therapy
includes stem cell-based and non-stem cell-based unicellular or multicellular therapies, as
well as a variety of different types of cells such as stem cells, lymphocytes, dendritic cells,
and pancreatic islet cells. In some cases, such as Chimeric Antigen Receptor – T (CAR-T)
and Chimeric Antigen Receptor – Natural Killer Cell (CAR-NK) cell therapies, cells are
genetically modified before they are (re)introduced into the patient. This technology
interlinks gene therapy and cell therapy. Gene editing techniques such as CRISPR-Cas9,
base editing, and prime editing may also be applied to correct genetic mutations and/or
14
Li, H., Yang, Y., Hong, W. et al. (2020). Applications of Genome Editing Technology in the Targeted Therapy
of Human Diseases: Mechanisms, Advances and Prospects’. Signal Transduction and Targeted Therapy, 5(1).
doi:10.1038/s41392-019-0089-y.
15
U.S. Food and Drug Administrative (2018). What is gene therapy? https://www.fda.gov/vaccines-blood-
biologics/cellular-gene-therapy-products/what-gene-therapy. Retrieved on 7 September 2023.
16
AstraZeneca (2023). Harnessing the Power of Cell Therapy https://www.astrazeneca.com/r-d/next-generation-
therapeutics/cell-therapies.html. Retrieved on 7 September 2023.
42
introduce beneficial edits in targeted stem cells. Gene-edited stem cells are currently and
increasingly investigated as a new therapeutic modality. Various studies have shown that
genome editing results in priming of stem cells for better therapeutic efficacy, delayed
disease progression, and protection against genetically driven diseases.1713
Figure 4.5: Schematic diagram showing different applications of gene editing, gene
therapy, and cell therapy1814
Similarities and differences between gene therapy and gene editing
4.7 Gene editing is employed in gene therapy where both targets the genetic cause of diseases,
such as a variant or mutation in a gene, and treat or halt progression of the disease using
genetic material. While both gene editing and gene therapy are used for therapeutic
purposes, gene editing does so by delivering genetic material or proteins that can directly
edit and change the information that the DNA encodes for to correct the protein produced
by the DNA and restore proper cellular function.1915Nonetheless, gene therapy delivers a
working gene into a cell using carriers like viral vectors, such as adeno-associated virus
(AAVs) and lentivirus vectors, or non-viral vectors such as liposomes to effect the therapy.
17
Lee, J. et al. (2020). Recent advances in genome editing of stem cells for drug discovery and therapeutic
application, Pharmacology & Therapeutics, 209. doi:10.1016/j.pharmthera.2020.107501.
18
The non-therapeutic applications of gene editing stated in the schematic diagram are examples and not
exhaustive.
19
NHS England (2023). What are Genome Editing and Gene
Therapy? https://www.genomicseducation.hee.nhs.uk/blog/what-are-genome-editing-and-gene-therapy/.
43
Gene therapy is solely used for therapeutic purposes, while gene editing has applications
beyond therapeutics, such as understanding disease development, conferring resistance, and
reducing predisposition to diseases, enhancement of traits, as well as other non-therapeutic
applications of technology underlying human gene editing.
Similarities and differences between cell therapy and gene editing
4.8 Both cell therapy and gene editing share the objective of modifying the underlying
biological mechanism of a disease, by either introducing functional cells (i.e., cell therapy),
or altering the genetic material of a living organism (i.e., gene editing). Gene editing
technologies, such as CRISPR-Cas9 in particular, are currently being used in cell therapies.
While cell therapy provides treatments for inherited or acquired diseases where whole cells
are infused or transplanted into a patient, gene editing corrects genetic diseases using
enzymes, particularly nucleases that have been engineered to target a specific DNA
sequence, and introduces cuts or chemical modifications into the DNA strands, such that the
existing DNA sequence may be changed to another sequence.
44
CHAPTER 5: POTENTIAL RESEARCH AND CLINICAL APPLICATIONS OF
HNGE AND CURRENT ESTABLISHED METHODS TO TREAT DISEASES
I. Potential Application of HNGE in Research to Understand Diseases or Cancer

Development
5.1 The inception of gene editing technologies has enabled enzymes such as nucleases to be
engineered as biological tools to introduce specific modifications at specific sites within the
genomic DNA. Such targeted gene modifications made using chimeric gene editing tools
(e.g., ZFNs, TALENs, and CRISPR-Cas9) are powerful methods to assess gene function as
well as precisely manipulate cellular behaviour and function. In particular, developments in
gene editing technologies have been leveraged on by investigators to understand the
aetiology behind various diseases and elucidate underlying molecular mechanisms that may
be used for better therapeutic strategies.
5.2 Gene editing technologies have been used in research for various purposes and indications.
Some examples of research conducted using gene editing technologies to understand
diseases and cancer development are discussed as follows:
a. Cancer research
5.3 Cancer arises as a result of genomic changes leading to the growth of tumour cells, where
undesirable mutations in the gene may lead to production of proteins harbouring aberrant
functions which result in uncontrolled cell growth. Gene editing tools such as CRISPR-Cas9
are being used in the field of cancer research to target specific regions of the genome within
the cancer cells to understand the causative mechanisms of tumorigenesis and development.
For instance, a study conducted in Japan in 2015 modelled colorectal cancer by introducing
multiple genetic mutations in human intestinal organoids using CRISPR-Cas9, which
allowed researchers to understand the mutation pathway driving cellular growth in the
tumour microenvironment.1 In a similar vein, CAR T-cells2 and CAR NK -cells3 have been
engineered using CRISPR-Cas9 to target tumour cells specifically. This area of research is
also receiving much attention in the pursuit of more effective treatment modalities in cancer.
b. Neurodegenerative Diseases
5.4 Neurodegenerative diseases (NDs), such as Alzheimer's, Huntington's, and Parkinson's
diseases, are debilitating conditions with poor prognosis and clinical outcomes due to the
lack of precise diagnostic tools and definite treatments. Studies have found that genetic
mutations are one of the causes of neurodegeneration. For example, familial Alzheimer’s
disease results from mutations in the amyloid precursor protein (APP) and presenilin
1
Matano, M. et al. (2015). Modeling colorectal cancer using CRISPR-Cas9–mediated engineering of human
intestinal organoids, Nature Medicine, 21(3), pp. 256–262. doi:10.1038/nm.3802.
2
Dimitri, A., Herbst, F. and Fraietta, J.A. (2022) ‘Engineering the next-generation of car T-cells with CRISPR-
Cas9 gene editing’, Molecular Cancer, 21(1). doi:10.1186/s12943-022-01559-z.
3
Pomeroy, E.J. et al., (2020). A genetically engineered primary human natural killer cell platform for cancer
immunotherapy, Molecular Therapy 28(1). doi:10.1016/j.ymthe.2019.10.009.
45
(PSEN1 and PSEN2) genes, which result in increased production of the amyloid-beta
protein responsible for the onset of the neurodegenerative disease.4 As such, gene editing
may offer a novel and promising tool to develop ND models for interrogating disease
mechanisms as well as discover potential drugs for treatment. In 2016, a research group in
Rockefeller University (US) generated human induced pluripotent stem cells (iPSCs) with
mutations in the APP and PSEN1 genes using CRISPR-Cas9 to study the early onset of the
disease.5
c. Hereditary Eye Diseases
5.5 Ocular diseases present with a variety of clinical manifestations, brought about by intrinsic
genetic mutations or external environmental factors. Gene-editing technologies have also
been used to probe the mechanisms of hereditary eye diseases.6 For example, a research
study carried out in China in 2018 employed genetic editing to investigate the molecular
mechanism of an inherited retinopathy, retinitis pigmentosa, due to mutation in a GTPase
regulator RPGR which resulted in disorders of the cones and rods in the eye. 7 They found
that the correction of the causative mutation in RPGR via CRISPR-Cas9 reverses ciliopathy
and rescues photoreceptor loss by restoring gene expression, demonstrating the use of
CRISPR-Cas9 as a mutation repair strategy.
II. Potential Application of HNGE in Research to Understand the Development of

Human Embryos
5.6 The use of human embryos in biomedical research has been touted to be beneficial in the
study of human embryo development and understanding of birth defects. In the context of
gene editing technologies, research involving human embryos may be carried out to
potentially discover and develop new treatments for genetic or complex diseases, enhance
longevity for healthy individuals by delaying ageing and produce designer babies. 8 In
particular, gene editing tools enable the uncovering of the role of specific genes in embryo
development in relation to physiology, disease development, pregnancy, and miscarriage.
By doing so, the underlying genetic causes of these maladies may be established to facilitate
the finding of new treatments.
5.7 Human embryos may also be used to construct new disease models for unravelling
pathologies of genetic diseases.9 Screening methods for drug discovery and development in
4
Lanoiselée, H.-M. et al. (2017). App, PSEN1, and PSEN2 mutations in early-onset alzheimer disease: A genetic
screening study of familial and sporadic cases, PLOS Medicine, 14(3). doi:10.1371/journal.pmed.1002270.
5
Kwart, D. et al. (2019). A large panel of isogenic app and PSEN1 mutant human IPSC neurons reveals shared
endosomal abnormalities mediated by app β-ctfs, not aβ, Neuron, 104(2). doi:10.1016/j.neuron.2019.07.010.
6
Sundaresan, Y. et al. (2023). Therapeutic applications of CRISPR/Cas9 gene editing technology for the
treatment of ocular diseases, The FEBS Journal . doi:10.1111/febs.16771.
7
Deng, W.L. et al. (2018). Gene correction reverses ciliopathy and photoreceptor loss in ipsc-derived retinal
organoids from retinitis pigmentosa patients, Stem Cell Reports, 10(4), pp. 1267–1281.
doi:10.1016/j.stemcr.2018.02.003.
8
Savulescu, J. (2015). Five reasons we should embrace gene-editing research on human embryos, Phys.org.
https://phys.org/news/2015-12-embrace-gene-editing-human-embryos.html. Retrieved on 23 January 2024.
9
Addie, S. et al. (2020) Stem Cell–Based Models of Human Embryos, Examining the state of the science of
Mammalian Embryo Model Systems: Proceedings of a workshop. Washington, DC: The National Academies
Press. https://www.ncbi.nlm.nih.gov/books/NBK560186. Retrieved on 23 January 2024.
46
human embryos may be developed for genetic diseases arising from exposure to toxic
substances and evaluate potential therapeutic agents for cure. However, it is imperative that
the use of gene editing technology for such purposes should be further refined and validated
before being considered as a therapeutic option.
5.8 Consistent with the use of human embryos for other research purposes, the 14-day rule
should be applied for any nuclear gene editing research carried out in human embryos. 10
The 14-day rule defines that biomedical research is allowed only in early human embryo
development.11 The rule is prescribed in science policy and regulation to limit all research
work carried out on human embryos up to a maximum of 14 days after their creation or to
the equivalent stage of development that is normally attributed to a 14-day-old embryo. In
view that there could potentially be further research development in gene editing for human
embryos, there would be a need to revisit and revise the scope and duration (i.e., beyond 14
days) of allowable research in early embryo development. Naturally, substantial efforts
would be required to conduct large scale stakeholder (e.g., legislators, medical practitioners,
and scientists) and public engagement to ensure that all views from the scientific and public
communities are taken into consideration before any changes to the 14-day rule are made.
5.9 In 2017, researchers from The Francis Crick Institute (UK) employed CRISPR–Cas9-
mediated gene editing to investigate the function of the pluripotency transcription factor
Octamer-binding transcription factor 4 (OCT4) during human embryogenesis.12 OCT4 was
specifically targeted in human zygotes (fertilised human eggs) and found to disrupt
blastocyst development. Such studies exemplify the potential of gene editing as a powerful
tool to study early human development.
III. Potential Application of Technology Underlying HNGE as Diagnostics and Drug

Discovery Tools
5.10 Rapid and accurate methods to diagnose diseases are equally and increasingly important to
detect the onset of symptoms and allow for early interventions. While nucleic-acid-based
sensors are the most specific and sensitive given that trace amounts of DNA and ribonucleic
acid (RNA) can be readily amplified and recognised via complementary base-pairing, such
technologies require costly equipment and skilled personnel.13 CRISPR-based diagnostics,
such as the CRISPR-Cas9 system, circumvent these issues through a target-specific binding
mechanism that is based on nucleotide sequence, and enables the technology to advance
diagnostic methods in detecting the disease-related gene, microRNAs, and genetic
variations such as single nucleotide polymorphism (SNP) and DNA methylation.
10
Singapore (2017) ‘No. S 622 Human Biomedical Research (Restricted Research) Regulations’.
https://sso.agc.gov.sg/SL/HBRA2015-S622-2017. Retrieved on 23 January 2024.
11
Blackshaw, B. P., & Rodger, D. (2021). Why we should not extend the 14-Day rule. Journal of Medical Ethics,
47(10), pp. 712–714. doi:10.1136/medethics-2021-107317.
12
Fogarty, N.M. et al. (2017). Genome editing reveals a role for OCT4 in human embryogenesis, Nature,
550(7674), pp. 67–73. doi:10.1038/nature24033.
13
Zhang, Z. et al. (2023). Functional nucleic acid-based biosensors for virus detection, Advanced Agrochem, 2(3),
pp. 246–257. doi:10.1016/j.aac.2023.07.006.
47
5.11 CRISPR-based diagnostics not only allow for a faster and more accurate diagnosis of
diseases in the clinic, but also bolster progress in the field of personalised medicine, such as
by enabling point-of-care testing (i.e., testing is done near a patient/person outside of the
clinical laboratory setting) by untrained personnel to be done at home. Broadly, CRISPR-
Cas9 diagnostics may be categorised into two classes, six types and several subtypes based
on evolutionary relationships. While applications of CRISPR as diagnostics are mostly still
in development, three notable ones are discussed here:
a. Diagnostic Tool: Specific high sensitivity enzymatic reporter UnLOCKing

(SHERLOCK)
5.12 SHERLOCK is a CRISPR-based diagnostic system that is guided by RNA, and was
developed in 2017 by the Broad Institute.14 The technology is able to identify low-frequency
mutations in cancer cells that are not easily identifiable by other sequencing methods, and
may be used to detect specific viral strains as well as differentiate between bacterial strains.
Similarly, in Nigeria where a Lassa fever epidemic has claimed the lives of approximately
69 people in 2019, a new CRISPR-based diagnostic test has been developed to detect the
viral infection.15 The test relies on CRISPR’s ability to detect RNA from the Lassa virus. If
the approach is successful, the test could be further programmed to detect a wide range of
viral infections including dengue, Zika and strains of the human papillomavirus (HPV),
allowing treatments to be administered early. Consequently, healthcare workers would be
able to curb the spread of infections.
b. Diagnostic Tool: DNA endonuclease targeted CRISPR trans reporter (DETECTR)
5.13 In 2018, a CRISPR-based diagnostic method, DETECTR, that harnesses the ability of the
Cas12a single-stranded DNase (ssDNase) to generate single-stranded DNA breaks was
developed in combination with isothermal amplification. 16 The diagnostic tool is highly
sensitive and has provided a simple platform for rapid and specific detection of human
papilloma virus (HPV) in patient samples, displaying promise in molecular diagnostics.
c. Personalised Treatment
5.14 CRISPR-Cas9-based screening for identification of new drug targets and biomarkers
presents an avenue in precision medicine. 17 This is particularly relevant for studies
involving cancer due to the heterogeneity in tumour cells and the underlying genetic causes
responsible for their resistance to drug treatment. Targeted gene editing approaches
employing CRISPR can not only be used in high-throughput screening to discover novel
14
Gootenberg, J.S. et al. (2017). Nucleic acid detection with CRISPR-CAS13A/C2C2, Science, 356(6336), pp.
438–442. doi:10.1126/science.aam9321.
15
Nesathurai, A. (2019). Lassa epidemic: Nigeria uses CRISPR to get early jump on viral outbreaks, Genetic
Literacy Project. https://geneticliteracyproject.org/2019/03/04/lassa-epidemic-nigeria-uses-crispr-to-get-early-
jump-on-viral-outbreaks/ Retrieved on 6 October 2023.
16
Chen, J.S. et al. (2018). CRISPR-CAS12A target binding unleashes indiscriminate single-stranded DNase
activity, Science, 360(6387), pp. 436–439. doi:10.1126/science.aar6245.
17
Xing, H. and Meng, L. (2019). CRISPR-Cas9: A powerful tool towards precision medicine in cancer
treatment, Acta Pharmacologica Sinica, 41(5), pp. 583–587. doi:10.1038/s41401-019-0322-9.
48
therapeutics but also in elucidating pathways driving drug resistance in cancer cells, and
ultimately leading to the development of personalised treatments for patients.
IV. Potential Application of HNGE for Genetic Enhancement to Confer Resistance to

Certain Diseases
5.15 Gene editing has been explored for its potential application in raising or conferring resistance
of individuals to diseases. This could be achieved by altering genes commonly found in the
general population to variants that are known or anticipated to be beneficial, thereby
enhancing certain traits of the individual. For instance, the β-globin (HBB) gene involved
in the genetic blood disorder beta-thalassaemia was first modified in zygotes in 2015.18
However, findings from the study showed low efficiency in genetic recombination as well
as genetic mosaicism and off-target cleavages. It is also worth noting that while gene editing
has been widely used for research in the area of treating diseases, there are possibilities for
the gene editing tools to be misused to prevent certain diseases or enhance certain features.
5.16 The controversy over the use of gene editing to confer resistance against disease could be
illustrated by the experiment conducted by He Jiankui in China that led to the birth of
genetically enhanced babies.19 He used CRISPR-Cas9 to modify the CCR5 gene in human
embryos with the intention to produce human babies with increased resistance to HIV
infections. CCR5 is a co-receptor expressed on the surface of immune cells involved in
signalling and coordination of immune responses, and it acts like a ‘door’ that allows the
HIV entrance into the cell, therefore playing an essential role in HIV pathogenesis. Mutation
in CCR5 gene locks “the door” which prevents HIV from entering into the cell.20 However,
He failed to consider the possible off-target effects of the technique used, the downstream
effects associated with heritable gene editing21, and the possible health risks to the babies in
the future, which led to criticisms for his risky conduct of ethically contentious and
medically unjustified procedure22 (see Chapter 12 ‘Genetic Enhancement and the Effects on
Society’ for a detailed discussion on the ethical issues). While the same approach to
introduce the mutation to the same gene in zygotes has been reported previously, mosaicism
and low efficiency of the gene editing were observed in the zygotes.23 Hence, the fidelity
and maturity of gene editing for the purpose of enhancing specific traits would need to be
clearly evaluated before the technology is approved for widespread use.
18
Liang P., et al. (2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell, 6, pp.
363–372. doi:10.1007/s13238-015-0153-5.
19
Normile, D. (2018). CRISPR bombshell: Chinese researcher claims to have created gene-edited twins.
https://www.science.org/content/article/crispr-bombshell-chinese-researcher-claims-have-created-gene-edited-
twins Retrieved on 6 October 2023.
20
Julia, P. (2013). HIV resistant mutation.
https://www.nature.com/scitable/blog/viruses101/hiv_resistant_mutation/#:~:text=The%20mutation%20causes
%20the%20CCR5,from%20entering%20into%20the%20cell Retrieved on 6 October 2023.
21
Tim, M. (2022). Are designer babies ethical? CRISPR and how to avoid the slippery slopes of heritable genetic
editing. The Lovepost. https://www.thelovepost.global/biotech-change/articles/are-designer-babies-ethical-
crispr-and-how-avoid-slippery-slopes-heritable Retrieved on 16 October 2023.
22
Hannah, D. (2023). Scientist who edited babies’ genes says he acted ‘too quickly’. The Guardian.
https://www.theguardian.com/science/2023/feb/04/scientist-edited-babies-genes-acted-too-quickly-he-jiankui
Retrieved on 16 October 2023.
23
Kang, X. et al. (2016). Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-
mediated genome editing, Journal of Assisted Reproduction and Genetics, 33(5), pp. 581–588.
doi:10.1007/s10815-016-0710-8.
49
V. Potential Application of HNGE for Polygenic Editing to Reduce Predisposition to
Diseases
5.17 Gene editing strategies developed or are being studied in clinical trials are largely for lethal
diseases that are typically associated with single nucleotide variants (SNVs) and are
relatively low in prevalence within the general population. Polygenic or complex diseases,
on the other hand, are attributed to multiple genetic variants. CRISPR may be used to
perform multiple edits to the gene simultaneously to address polygenic diseases caused by
the combined action of more than one genetic variant or mutation.24
5.18 Multi-gene editing has been reported in several instances. In 2022, engineers in the Rice
University developed the “drive and process” (DAP) array, which is a streamlined CRISPR-
based technology that is able to correct dozens of errors at the same time with high precision
and efficiency.25 The approach is time-efficient and has been shown to work in human cell
models for heart disease, Type 2 diabetes, muscular dystrophy, sickle cell disease and beta
thalassaemia caused by a combination of mutations. Separately, Verve Therapeutics
announced in July 2022 that a clinical trial will be conducted for their gene therapy,
VERVE-101.26 The first-in-class gene editor converts an adenine base to a guanine base
within the gene encoding a protein called PCSK9, which is a key regulator of blood
cholesterol levels. Disabling PCSK9 has been shown to reduce cholesterol levels and, by
extension, the risk of heart diseases. Therefore, the trial aims to study the efficacy of
lowering levels of functional PCSK9 in individuals with heterozygous
hypercholesterolaemia, a condition that causes high cholesterol which may lead to cardiac
complications.
VI. Potential Application of HNGE to Correct Disease-causing Mutations as a

Therapeutic Strategy
5.19 Gene editing for treatment of diseases is widely studied for its potential to correct aberrant
genetic mutations with high precision and accuracy. Gene editing tools such as CRISPR are
not only employed to study mutations in disease-causing genes, but more importantly, they
can be used to correct the mutations for treatment of diseases, which are discussed as
follows:
a. Human Immunodeficiency Virus (HIV)
24
Guo, N. et al. (2022). The power and the promise of CRISPR/Cas9 genome editing for clinical application with
gene therapy, Journal of Advanced Research, 40, pp. 135–152. doi:10.1016/j.jare.2021.11.018.
25
Rice University (2022). CRISPR-based strategy edits multiple genes and could treat polygenic diseases.
ScienceDaily. www.sciencedaily.com/releases/2022/05/220519115354.htm Retrieved on 6 October 2023.
26
Verve Therapeutics (2022). Verve Therapeutics Doses First Human with an Investigational In Vivo Base
Editing Medicine, VERVE-101, as a Potential Treatment for Heterozygous Familial Hypercholesterolemia.
https://ir.vervetx.com/news-releases/news-release-details/verve-therapeutics-doses-first-human-investigational-
vivo-base Retrieved on 6 October 2023.
50
5.20 HIV is a major public health concern, where millions are infected and many die from its
complications every year. 27 However, there is no effective vaccine and cure for HIV
infections. The current prescribed treatment for HIV infections involves combination
antiretroviral therapy (cART), which targets the replication cycle of the HIV virus, and is a
life-long treatment.28 The development of anti-HIV therapy is challenging primarily due to
the poor understanding of HIV reservoirs, from which the virus may persist and regenerate
upon integration into the cellular genome. Gene therapy, which is used to target and
inactivate integrated viral genomes, provides an alternative to achieve a functional HIV
cure. For example, a research conducted in the US in 2014 studied the NHEJ-mediated
inactivation of the CCR5 gene in autologous CD4 T-cells of persons infected with HIV
using ZFNs. 29 The study found that infusion of the CCR5-modified CD4 T-cells was
feasible and generally safe, although limited by the small sample size.
b. Spinocerebellar Ataxia
5.21 Spinocerebellar ataxia refers to a class of rare neurodegenerative diseases that is autosomal
dominantly inherited and manifests in loss of various cognitive and motor functions. 30
Potential treatment options for the disease typically include pharmacological interventions
as well as speech and physiotherapy. Most conditions associated with spinocerebellar ataxia
are caused by higher than normal levels of genetic sequence coding for glutamine due to
polyglutamine-encoding repeat expansions within the gene, which results in protein
aggregation and cell death.31 This may be corrected by gene editing. A study conducted in
China in 2021 demonstrated the feasibility of CRISPR-Cas9-mediated homologous
recombination strategy to precisely repair spinocerebellar ataxia type 3 in iPSCs and reverse
the corresponding abnormal disease phenotypes such as mitochondrial dysfunction and
oxidative stress disorders.32
c. Spinal Muscular Atrophy (SMA)
5.22 Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in the
survival motor neuron 1 (SMN1) gene where outcomes of existing therapies have been
suboptimal. 33 Gene editing may be employed to restore the levels of SMN protein
27
Joint United Nations Programme on HIV/AIDS. (n.d.). Global HIV & AIDS statistics - fact sheet, UNAIDS.
https://www.unaids.org/en/resources/fact-sheet#:~:text=Since%202010%2C%20new%20HIV%20infections,–
210%20000%5D%20in%202022 Retrieved on 6 October 2023.
28
Hussein, M. et al. (2023). A CRISPR-Cas Cure for HIV/AIDS, International Journal of Molecular Sciences,
24(2), p. 1563. doi:10.3390/ijms24021563.
29
Tebas, P. et al. (2014). Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV, New
England Journal of Medicine, 370(10), pp. 901–910. doi:10.1056/nejmoa1300662.
30
Ghanekar, S.D. et al. (2022). Current and emerging treatment modalities for spinocerebellar ataxias, Expert
Review of Neurotherapeutics, 22(2), pp. 101–114. doi:10.1080/14737175.2022.2029703.
31
Sagar, D. et al. (2005). Molecular origin of polyglutamine aggregation in neurodegenerative diseases, PLoS
Computational Biology, 1(3), p. 30. doi:10.1371/journal.pcbi.0010030.
32
He, L. et al. (2021). CRISPR/Cas9 mediated gene correction ameliorates abnormal phenotypes in
spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cells, Translational Psychiatry, 11(1).
doi:10.1038/s41398-021-01605-2.
33
Alves, C.R. et al. (2023). Base editing as a genetic treatment for spinal muscular atrophy, BioRxiv Preprint.
doi:10.1101/2023.01.20.524978.
51
expression by precisely editing survival motor neuron 2 (SMN2), possibly delivering a new
treatment option for SMA. For instance, the US Food and Drug Administration (FDA)
approved the first gene therapy onasemnogene abeparvovec (or ZolgensmaTM) for the
treatment of SMA for children under 2 years of age. 34 ZolgensmaTM is a biologic
administered intravenously to deliver the SMN1 transgene as well as synthetic promoters,
using viral capsids as delivery vectors, that could promote the expression of functional SMN
and improve muscle activity in a child with SMA.
d. β-thalassaemia
5.23 β-thalassaemia is a genetic blood disorder caused by β-chain deficiency in haemoglobin

production. The standard treatment for β-thalassaemia is allogeneic bone marrow
transplantation (BMT) from a completely matched donor, which requires long-term use of
immunosuppressants and may invoke other immunological complications such as higher
susceptibility to infections as well as graft-versus-host diseases.35 Gene editing applied to
β-thalassaemia can treat the disease without involving the use of immunosuppressants and
graft-versus-host disease prophylaxis, garnering attention to the modality for treatment of
this disease.36 For example, the first attempt to correct mutation in the HBB gene responsible
for β-thalassaemia in human embryos was reported in a study conducted in China in 2017.36
The CRISPR-adapted base-editing tool was shown to precisely modify the HBB gene with
efficiency of over 23% and repaired more than 20% of the blastomeres. The study however
observed mosaicism in the edited embryos. In 2019, Allife Medical Science and Technology
Co., Ltd. conducted a clinical trial for the application of CRISPR-Cas9 for the treatment of
β-thalassaemia. In the study, the HBB gene was corrected in induced haematopoietic stem
cells (iHSCs) derived from patients and transfused intravenously back to the subjects,
demonstrating the potential of gene therapy for β-thalassaemia.
VII. Current Established Methods of Treatment/ Prevention of Diseases in Individuals

or Offspring
5.24 This section will only discuss the scientific and medical advantages and disadvantages of
the current established methods of treating or preventing diseases in individuals or future
offsprings. The ethical issues involved in the applications of HNGE would be discussed in-
depth in the subsequent chapters (i.e., from Chapters 6 to 10).
a. Conventional treatments
34
Mahajan, R. (2019). Onasemnogene Abeparvovec for spinal muscular atrophy: The Costlier Drug
Ever, International Journal of Applied and Basic Medical Research, 9(3), p. 127.
doi:10.4103/ijabmr.ijabmr_190_19.
35
Rahimmanesh, I. et al. (2022). Gene editing-based technologies for beta-hemoglobinopathies
treatment, Biology, 11(6), p. 862. doi:10.3390/biology11060862.
36
Liang, P. et al. (2017). Correction of β-thalassemia mutant by base editor in human embryos, Protein & Cell,
8(11), pp. 811–822. doi:10.1007/s13238-017-0475-6.
52
5.25 While gene editing offers new and promising strategies to the treatment of severe diseases
which lack effective cures in most cases, the technology is still in development and requires
deep scrutiny prior to approval for widespread clinical applications. Hence, conventional
treatments (e.g., chemotherapy, radiation, or surgery for cancer) remain the primary choice
of therapy or clinical management, even though the safety and efficacy of non-heritable
gene editing is more well-established than heritable gene editing.
5.26 Conventional treatments are generally regarded to be safe for clinical use and had
demonstrated good clinical efficacy given that they have been put through rigorous
scientific testing and clinical trials. Therefore, prescribing treatment regimens with
conventional therapies and established management or procedures would be desirable for
patients. However, conventional treatments may not be effective in patients who have
developed resistance to treatments (e.g., chemotherapy resistance in cancer), and hence,
other forms of therapeutics such as gene editing may be required.
b. Prenatal testing or No testing
5.27 Prenatal testing refers to tests carried out during pregnancy to assess a pregnant woman and
her foetus’ health, and primarily consists of prenatal screening and prenatal diagnosis.37
Screening tests are used to identify the likelihood of abnormalities of the foetus (e.g., birth
defects and genetic disorders) while diagnostic tests are invasive tests that confirm the
preliminary outcomes obtained from the screening test. Prenatal tests comprise maternal
blood or saliva tests, urine tests, ultrasound (including nuchal translucency), amniocentesis,
chorionic villus sampling (CVS), and percutaneous umbilical blood sampling (PUBS) (also
known as Foetal Blood Sampling (FBS)). Alternatively, parents may also choose not to
undergo any prenatal testing for such abnormalities.
5.28 Prenatal testing assures parents of the foetus’s condition and allows them to obtain
information about the possibility of predispositions for certain genetic conditions to develop
in the foetus prior to birth.38 This allows the parents to decide on the follow-up actions
required, such as consulting a specialist doctor for medical advice, consideration for foetal
therapy if applicable39, and appropriate preparation for birth of an affected baby. Parents
may also choose not to take any further actions and continue pregnancy as usual. Prenatal
testing also informs and provides parents with the option for therapeutic termination of an
affected foetus (i.e., interruption of pregnancy), if necessary.
5.29 However, specific types of prenatal diagnostic testing (e.g., amniocentesis, CVS, PUBS) are
invasive and involve inserting a thin catheter or needle either through the abdomen or the
cervix to collect samples of amniotic fluid or placental tissue.40 While it is dependent on the
37
Mayo Clinic (2022). Prenatal testing: Is it right for you? https://www.mayoclinic.org/healthy-
lifestyle/pregnancy-week-by-week/in-depth/prenatal-testing/art-20045177 Retrieved on 6 October 2023.
38
Women’s Health Institute. (2023). The benefits of prenatal testing. https://www.whisanantonio.com/the-
benefits-of-prenatal-testing/ Retrieved on 6 October 2023.
39
Sparks T.N. (2021). The current state and future of fetal therapies. Clinical Obstetrics and Gynecology, 64(4):
926-932. doi:10.1097/GRF.0000000000000651.
40
Bringman, J.J. (2014). Invasive prenatal genetic testing: A Catholic healthcare provider’s perspective, The
Linacre Quarterly, 81(4), pp. 302–313. doi:10.1179/2050854914y.0000000022.
53
specific type of test employed, such procedures are generally accompanied with an
increased risk of miscarriage and other pregnancy complications. For instance, the rate of
miscarriage with amniocentesis is about 1 in 200, and carries a low risk of uterine infection,
which could also lead to miscarriage, leakage of amniotic fluid, and injury to the foetus.41
The rate of miscarriage with CVS is approximately less than 1 in every 200, or slightly
higher than that of amniocentesis.42 In PUBS (i.e., FBS), the rate of miscarriage is about 1
to 2 of every 100 procedures, where the test could result in bleeding from the foetal blood
sampling site, leaking of amniotic fluid, and infection.43 While there are available tests such
as non-invasive prenatal testing (NIPT) which are non-invasive, these tests are primarily
used for screening purposes and would require confirmatory diagnostic tests.44 For example,
NIPT primarily screens for common chromosomal conditions but is unable to detect genetic
or structural abnormalities or other birth defects. A certain amount of cell-free foetal DNA
(cffDNA) is also required in the maternal blood for a test result to be generated.
5.30 Despite the benefits of prenatal screening testing for parents, results obtained from the tests
may not always be reliable, and such errors in results may lead to failure in identifying birth
defects accurately. Prenatal testing can also be expensive, costing anywhere from a few
hundred dollars to several thousand dollars, depending on the type of screening or diagnostic
test used. Generally, non-invasive tests such as maternal blood testing and ultrasound (e.g.,
combined first trimester screening) are more affordable 45 than invasive tests such as
amniocentesis, CVS, and PUBS. It should also be noted that termination of pregnancy is
prohibited after 24 weeks of gestation in Singapore, except under the circumstances for
which the mother’s life is in danger.46 Therefore, the prenatal diagnosis test must be done
within this window period if the parents are considering the option of therapeutic
termination of an affected foetus.
c. Adoption
5.31 Adoption is a legal process by which an individual takes over the parenting of a child from
his or her biological or legal parents. It is a long-term commitment and responsibility for
the upbringing of a child, which distinguishes from other types of relationships, such as
fostering, a temporary care arrangement where the foster children remain the legal children
of their natural parents.
41
March of Dimes (2017). Amniocentesis. https://www.marchofdimes.org/find-support/topics/planning-
baby/amniocentesis Retrieved on 6 October 2023.
42
National Health Service (NHS) UK. (2023). Chorionic Villus Sampling:
Complications. https://www.nhs.uk/conditions/chorionic-villus-sampling-cvs/risks/. Retrieved on 25 January
2024.
43
Ghidini, A. et al. (1993). Complications of fetal blood sampling, American Journal of Obstetrics and
Gynecology, 168(5), pp. 1339–1344. doi:10.1016/s0002-9378(11)90761-3.
44
Jayashankar S.S. et al. (2023) Non-Invasive Prenatal Testing (NIPT): Reliability, Challenges, and Future
Directions. Diagnostics (Basel), 13(15): 2570. doi:10.3390/diagnostics13152570.
45
Tan, T. (2015). Combined first trimester screen or noninvasive prenatal testing or both, Singapore Medical
Journal, 56(01), pp. 1–3. doi:10.11622/smedj.2015001.
46
Ministry of Health Singapore (2004). Guidelines on termination of pregnancy.
https://www.moh.gov.sg/docs/librariesprovider4/default-document-library/(2)_guidelines-on-termination-of-
pregnancy.pdf Retrieved on 6 October 2023.
54
5.32 Adoption provides couples, who are unable to produce children that are genetically healthy,
an opportunity to complete their family. However, it remains that these couples do not share
a biological link with the adopted child.47
d. Selective termination of pregnancy
5.33 Selective termination is primarily used to prevent or reduce the complications caused by the
birth of an affected foetus(es), particularly in higher-order multiple pregnancies, and
increases the survival odds of the remaining foetus(es). Multifoetal gestations (e.g., twins,
triplets, and higher-order multiples) are often at a higher risk for various maternal, foetal,
and neonatal complications, as compared to singleton pregnancies, which attribute to a
higher proportion of preterm births.48 For instance, neurodevelopmental morbidity such as
cerebral palsy in twin births or higher-order pregnancies are markedly higher than that in
singleton births. Besides multifoetal pregnancy reduction (MPR), which is used to reduce
the number of foetuses in the gestation and improve maternal and survival outcomes of the
foetus(es), selective termination involves reducing the foetal number by removing the
foetus(es) with known genetic, structural, or other abnormality identified during prenatal
testing.49
5.34 However, the procedure is also accompanied by risks, such as retained placenta50, infection,
miscarriage, and pre-labour rupture of membranes.51
e. Embryo selection
5.35 During in-vitro fertilisation (IVF), multiple embryos are created to increase the likelihood
of obtaining a viable embryo. However, the chance of a viable embryo to be successfully
implanted is subjected to various factors including biological variation.52 Pre-implantation
genetic testing for monogenic/single gene defects (PGT-M), pre-implantation genetic
testing for chromosomal structural rearrangements (PGT-SR) or pre-implantation genetic
testing for aneuploidies (PGT-A) is used to test and diagnose embryos for specific genetic
or chromosomal abnormalities. 53 The embryo that is not affected with the genetic
dysfunctionality tested for will be selected and implanted into the woman’s uterus to
maximise the chance of successful and normal pregnancy. Hence, PGT-M/SR/A reduces
47
Brodzinsky, D.M. (2011). Children’s Understanding of Adoption: Developmental and Clinical
Implications, Professional Psychology: Research and Practice, 42(2), pp. 200–207. doi:10.1037/a0022415.
48
Beriwal, S., Impey, L. and Ioannou, C. (2020). Multifetal pregnancy reduction and selective termination, The
Obstetrician & Gynaecologist, 22(4), pp. 284–292. doi:10.1111/tog.12690.
49
Rochon, M. and Stone, J. (2022). Multifetal pregnancy reduction and selective termination, UpToDate.
https://www.uptodate.com/contents/multifetal-pregnancy-reduction-and-selective-termination Retrieved on 6
October 2023.
50
Weiran, Z. et al. (2021). Retained placenta creta after selective fetal reduction in twin pregnancy: a case report.
https://mednexus.org/doi/full/10.1097/FM9.0000000000000117. Retrieved on 25 January 2024.
51
Miremberg, H. et al. (2023). Adverse outcome following selective termination of presenting twin vs non-
presenting twin, Ultrasound in Obstetrics & Gynecology, 61(6), pp. 705-709. doi: 10.1002/uog.26170.
52
Mastenbroek, S. et al. (2011). Embryo selection in IVF, Human Reproduction, 26(5), pp. 964–966.
doi:10.1093/humrep/der050.
53
Elpida, F. (2007). Preimplantation genetic diagnosis: present and future, Journal of assisted reproduction and
genetics, 24(6), pp: 201 – 207. doi: 10.1007/s10815-007-9112-2.
55
the risk of passing on inherited conditions or genetic disorders and allows couples to avoid
an abnormal pregnancy.
5.36 Unlike gene editing which may cause unintentional mutation(s) to be passed down to future
offspring, embryo selection is deemed to be safer as PGT-M/SR/A does not cause genetic
aberrations in the embryo while enabling couples to have a genetically identical child
without the inherited genetic disorder. However, embryo selection is limited and may not
be a feasible option in situations where all or majority of embryos are affected from genetic
dysfunctionality. This is relevant in the case of Huntington's disease, where all embryos
would carry the dominant disease-causing allele. In polygenic conditions caused by the
combination of two different mutations in a gene, and combinations of specific alleles of
two or more genes, it may be challenging to select embryos by PGT-M/SR/A and thus render
limited use.
f. Donated gametes
5.37 Use of donated gametes may be helpful particularly in cases where the couple’s sperms
and/or eggs are not sufficiently healthy to lead to successful pregnancy, or when one or both
parents are affected by genetic condition(s), which may prevent or affect the birth of the
child.
5.38 Using donated eggs or sperms allows one of the intended parents to maintain the genetic
relationship with the child, while avoiding the propagation of any inherited condition that
may be passed down to the child. Furthermore, the procedures involved (i.e., intrauterine
insemination and IVF) are simple, safe, and has low risk of serious complications. However,
unlike donated eggs or sperms, using donated embryos from others does not allow either of
the intended parents to have children that are genetically associated with them.
g. Intrauterine foetal gene therapy
5.39 Gene editing technologies may be used to treat monogenic disorders in foetus(es) via
intrauterine foetal gene therapy.54 The procedure involves injecting the therapeutic agent
(e.g., vectors encoding therapeutic genes) into an umbilical blood vessel, the amniotic fluid
or occasionally directly into foetal tissue, with the guidance of an ultrasound probe. While
intrauterine foetal gene therapy is currently not available for clinical use, it might be a
possible alternative to heritable gene editing for fertility issues in the future.
5.40 Foetal gene therapy can be employed to treat monogenic disorders prior to the pathological
development of the disease, thus significantly decreasing morbidity and mortality. Unlike
heritable gene editing, foetal gene therapy has the advantage of robust preclinical data.
Several clinical trials in animal models have shown that viral vectors are efficient vehicles
in foetal gene therapy, therefore making foetal gene therapy a promising alternative to
heritable gene editing. However, similar to other genetic modifying technologies, foetal
54
Mattar, C.N. et al. (2021). Ethical considerations of preconception and prenatal gene modification in the
embryo and fetus, Human Reproduction, 36(12), pp. 3018–3027. doi:10.1093/humrep/deab222.
56
gene therapy may cause insertional mutagenesis, oncogenesis, genetic mutation transfer
from mother to child and foetal disruption.
5.41 The applications of HNGE stretches across various indications and may be used in
investigative studies of diseases, enhancement of specific traits, therapeutic intervention,
diagnosis of diseases as well as treatment of fertility. However, many findings reported by
research groups aforementioned are largely preliminary and necessitate further studies to
determine the long-term safety and efficacy of gene editing technologies. Studies pertaining
to the difference in idiosyncratic effects due to individual genetic variations should also be
taken into consideration. Therefore, until the safety and efficacy of HNGE technologies are
demonstrated in pre-clinical studies and in clinical trials approved under regulated clinical
trial framework, the current established methods would be preferred to treat or prevent
diseases in individuals and future offsprings.
57
CHAPTER 6: MOSAICISM, OFF-TARGET EFFECTS, AND ON-TARGET
UNDESIRABLE MODIFICATIONS
6.1 Targeted modifications to nuclear DNA and gene editing technologies have the potential to
prevent, treat, or cure certain inherited genetic disorders, 1 and might even be used to
enhance traits and confer resistance to diseases. When used in a controlled manner,
corrections to the genomic sequence could be carried out with precision using molecular
scissors, which are mostly enzyme-based, to rectify or remove mutations that could
otherwise lead to deleterious health conditions.2 Such technologies could lead to unintended
biological outcomes such as chromosomal mosaicism in embryos, and undesirable
consequences arising from off-target mutations and deletions.1 This chapter discusses the
ethical principles of proportionality, sustainability, solidarity and responsible stewardship
of science, the ethical issues of chromosomal mosaicism, off-target effects, and on-target
undesirable modifications, and their impact to individuals and the society, which would be
important considerations for potential applications of HNGE.
Issue 1: Chromosomal mosaicism in embryos and miscarriage
6.2 Chromosomal mosaicism is a condition that occurs when a person has two or more sets of
cells that differ genetically from one another. For example, a person with this condition
might possess some cells that have 46 chromosomes while other cells have 47 chromosomes.
This phenomenon may occur when gene editing is conducted on embryos beyond the single-
cell stage (i.e., after significant DNA replication and cell division take place)3. It can lead
to genetic disease if the abnormal cells begin to outnumber the normal cells, thereby
undermining disease prevention. With technological improvements and better
understanding of gene editing mechanisms, chromosomal mosaicism in embryos could be
reduced with more precise modifications or adjustments in dosage regimens.4 However,
with current technology, it remains highly possible that chromosomal mosaicism in embryos
could lead to preimplantation embryo wastage, miscarriages, and increased risk of birth
disorders and genetic diseases, given that there are no current non-destructive method to
determine whether all the cells in the embryo carry exactly the same edits. 3 Physiological
defects arising from the genetic aberrations could potentially be passed on to future
generations, who may be inflicted with severe genetic diseases that could be more fatal than
the initial benign condition that was meant to be treated by the genetic modification.
Therefore, researchers are advised to consider the following ethical principles when
conducting heritable genome editing for the treatment of diseases, conferring resistance,
enhancement of traits or for infertility (if permitted in the future):
a. Proportionality
1
Li, H. et al. (2020). Applications of genome editing technology in the targeted therapy of human diseases:
Mechanisms, advances and prospects. Signal Transduction and Targeted Therapy, 5(1). doi:10.1038/s41392-019-
0089-y.
2
Broeders, M. et al., (2020). Sharpening the molecular scissors: Advances in gene-editing technology. iScience,
23(1): 100789. doi:10.1016/j.isci.2019.100789.
3
National Academies Press (US). (2020). Heritable Human Genome Editing. Chapter 2: The State of Science.
https://www.ncbi.nlm.nih.gov/books/NBK565923. Retrieved on 26 October 2023.
4
Lamas-Toranzo, I. et al. (2019) Strategies to reduce genetic mosaicism following CRISPR-mediated genome
edition in bovine embryos. Scientific Reports, 9(1). doi:10.1038/s41598-019-51366-8.
58
6.3 The principle of proportionality requires researchers to ensure that the risks of HNGE
biomedical research and clinical applications are not disproportionate to their benefits by
minimising the harm to individuals and future offspring while maximising benefits using
heritable gene editing technologies for treatment of diseases, conferring resistance,
enhancement of traits, or for treatment of infertility. With the lack of sufficient safety and
efficacy data for interventions employing heritable gene editing, the existence of
chromosomal mosaicism as a result of inaccuracy or imprecision in such techniques could
pose harm to the individual receiving the treatment. This could outweigh the benefits of the
therapy.5 Medical interventions for infertility employing heritable gene editing could also
have ramifications on the prospective mother as the risk of miscarriage due to chromosomal
mosaicism in embryos could outweigh the perceived benefits (i.e., correction of mutations
in germ cells that could possibly treat infertility to enable pregnancy). The risk of
miscarriage could be attributed to abnormalities in the chromosomes which occur because
of aberrant cell division and growth.6 Miscarriages might also lead to further complications
such as psychological distress and future risk of infertility for the mother. Therefore,
heritable gene editing for treatment of diseases, conferring resistance, enhancement of traits
or for infertility should be considered only if scientific and technological advancements are
able to reduce mosaicism or mitigate the effects of mosaicism.
b. Sustainability
6.4 The principle of sustainability provides that the use of HNGE in biomedical research and
clinical applications should not harm the offspring and its future generations. Given that
gene editing technologies have the potential to result in chromosomal mosaicism,
implanting or transferring mosaic embryos could lead to an increased risk for a child to be
born with a chromosome disorder. This may potentially compromise the welfare of the
offspring. While more than 100 live births have been documented with reassuring outcomes
and no abnormal phenotype after mosaic embryo transfer, there are questions that remain
unanswered, such as the long-term outcomes of infants born via mosaic embryo transfer7.
Therefore, it would be important to validate the safety and efficacy of gene editing
technologies before they are used for clinical applications involving heritable gene editing.
c. Solidarity
6.5 The principle of solidarity maintains that benefits harnessed from research and applications
of HNGE involving altruistic participation from individuals should extend to the society and
that risks should be minimised. Given that heritable gene editing for treatment of diseases,
conferring resistance, enhancement of traits or for infertility have the possibility to result in
chromosomal mosaicism and miscarriages, research participants and people undergoing
such procedures may be exposed to harm that could also affect the future generations. The
5
Mehravar, M. et al., Shirazi, A., Nazari, M., & Banan, M. (2019). Mosaicism in CRISPR/cas9-mediated genome
editing. Developmental Biology, 445(2), pp 156–162. https://doi.org/10.1016/j.ydbio.2018.10.008
6
Yang, G. et al. (2022) Comparison of chromosomal status in reserved multiple displacement amplification
products of embryos that resulted in miscarriages or live births: A blinded, nonselection case–Control Study. BMC
Medical Genomics, 15(1). doi:10.1186/s12920-022-01187-y.
7
Sina, A, and Jennifer, F.K. (2021). Pregnancy and Neonatal Outcomes after Transfer of Mosaic Embryos: A
Review. Journal of Clinical Medicine, 10(7). doi:10.3390/jcm10071369.
59
principle of solidarity and consideration of the public good deserve greater consideration in
making sure that advances in HNGE become shared benefits.8 Hence, heritable gene editing
should not be conducted until they are proved to be safe and beneficial to the research
participants and the society.
Consideration: The above issue may not be applicable to embryos that would not have
existed if gene editing was not performed, or to embryos that were affected by genetic
mutations leading to catastrophic conditions. The risk of mosaicism may not outweigh
the risks involved if the embryos do not undergo gene editing, and therefore heritable
gene editing may be attempted for such cases.
Issue 2: Off-target mutations, deletions, and rearrangements in DNA

6.6 While HNGE introduces desired changes at the intended target sequence, unintended
modifications could be introduced elsewhere in the genome. This is known as off-target
effects. The ability to reduce the frequency of unwanted changes and the ability to detect
off-target mutations when they occur have both progressed in recent years, where
frequencies of off-target mutagenesis below 0.01 percent at individual at-risk sites have
been achieved in some cases.3 However, current tools in gene editing (heritable or non-
heritable) still harbour the possibility of causing DNA deletions and rearrangements which
can eventually lead to genome instability and disruption of the functional genes.9 As such,
this may result in aberrant cell cycles, unprecedented changes in gene expression and
regulation. 10 Risk of further complications such as development of cancer and allergic
reactions, would be dependent on the type of gene editing approach employed as well as the
adverse reactions associated with the modality. 11 Therefore, researchers are advised to
consider the following ethical principles when conducting non-heritable and heritable gene
editing (if permitted in the future) for clinical applications:
a. Proportionality
6.7 The principle of proportionality provides that the risks of clinical applications involving
HNGE are not disproportionate to their benefits by minimising the harm to individuals and
future offspring while maximising benefits. While modern gene editing tools may alleviate
some safety concerns due to the targeted nature of the technology, other concerns persist,
such as the potential for off-target effects that could result in harmful consequences for
8
John, J. M, Benjamin, C., et. al. (2017). Ethical Issues of CRISPR technology and gene editing through the lens
of solidarity. British Medical Bulletin, 122, pp 17 – 29. doi; 10.1093/bmb/ldx002.
9
Rayner, E. et al. (2019). CRISPR-Cas9 causes chromosomal instability and rearrangements in cancer cell lines,
detectable by cytogenetic methods. The CRISPR Journal, 2(6), pp. 406–416. doi:10.1089/crispr.2019.0006.
10
Begley, S. (2018). CRISPR-edited cells linked to cancer risk in 2 studies, Scientific American.
https://www.scientificamerican.com/article/crispr-edited-cells-linked-to-cancer-risk-in-2-studies/. Retrieved on
26 October 2023.
11
National Hearth, Lung, and Blood Institute (2022). Genetic Therapies. Benefits and Risks.
https://www.nhlbi.nih.gov/health/genetic-therapies/benefits-
risks#:~:text=Potential%20risks%20could%20include%20certain,use%20in%20the%20United%20States.
Retrieved on 1 November 2023.
60
healthy gene function12 and affect the health and well-being of patients undergoing clinical
trials on non-heritable gene editing13. These consequences could outweigh the benefits of
non-heritable gene editing, such as correction of disease-causing mutations. Researchers
and clinicians are thus obligated to ensure a favourable risk-benefit ratio for patients
undergoing HNGE clinical trials, and should ensure that clinical trials on non-heritable gene
editing are designed to minimise any unprecedented harmful effects to patients. However,
this would be challenging to achieve in the short-term, given the lack of understanding of
the extent to which non-heritable gene editing can cause unintended secondary edits in the
target genome.14 Therefore, it would be essential for further studies on non-heritable gene
editing to be conducted to fully understand the unintended consequences of HNGE.
b. Sustainability
6.8 The principle of sustainability provides that clinical applications of HNGE should ensure
that adverse effects or harm rendered by the use of the technology are not perpetuated to
future generations. Although heritable gene editing holds promise in preventing and treating
debilitating inherited diseases, and enabling infertile couples to conceive children, a study
at Oregon Health and Science University reveals that gene editing to correct disease-causing
mutations in early human embryos could lead to unintended and potentially harmful changes
in the genome. 15 This unintended effect could be passed on to future offspring and
jeopardise their well-being. In another research, by researchers at Columbia University, that
aimed at fixing defective DNA in human embryos using CRISPR-Cas9, it was found that
the editing caused unintended changes, such as loss of an entire chromosome in more than
half of the embryos experimented on. 16 These changes could be passed on to future
generations if the embryos are used to establish pregnancy, indicating that it is too early to
know whether heritable gene editing can be done safely. Therefore, more research would
need to be conducted to develop methods to mitigate off-target effects and other unintended
mutations as a result of heritable gene editing on human embryos before gene-editing
established pregnancy can be deemed safe.
c. Responsible stewardship of science
6.9 The principle of responsible stewardship of science refers to the moral requirement of
researchers to be prudent about the resources utilised in the pursuit of HNGE research and
bear in mind the ethical guidelines governing its application. This includes setting research
12
PHG Foundation (2023). Somatic genome editing: ethics and regulation.
https://www.phgfoundation.org/briefing/somatic-genome-editing-ethics-regulation. Retrieved on 26 October
2023.
13
Li, H., Yang, Y., Hong, W., Huang, M., Wu, M., & Zhao, X. (2020). Applications of genome editing technology
in the targeted therapy of human diseases: Mechanisms, advances and prospects. Signal Transduction and
Targeted Therapy, 5(1). https://doi.org/10.1038/s41392-019-0089-y
14
Khoshandam, M. et al. (2024) Clinical applications of the CRISPR/cas9 genome-editing system: Delivery
Options and challenges in Precision Medicine. Genes & Diseases, 11(1), pp. 268–282.
doi:10.1016/j.gendis.2023.02.027.
15
Erik, R. (2023). Study reveals limitations in evaluating gene editing technology in human embryos.
https://news.ohsu.edu/2023/03/07/study-reveals-limitations-in-evaluating-gene-editing-technology-in-human-
embryos#:~:text=In%20addition%2C%20the%20study%20reveals,harmful%20changes%20in%20the%20geno
me. Retrieved on 26 October 2023.
16
Associated Press. (2020). Lab tests show risks of using CRISPR gene editing on embryos.
https://www.statnews.com/2020/10/29/lab-tests-show-risks-of-using-crispr-gene-editing-on-embryos/. Retrieved
on 26 October 2023.
61
priorities while considering the needs of the society so that social and scientific benefits are
maximised, and potential risks are minimised. Researchers have been developing strategies
to prevent or reduce the occurrence of existing errors arising from HNGE. For instance,
gene editing tools with greater precision, such as base editors, have been investigated in
preclinical disease models to determine their editing efficiencies and accuracy.17 Patients
undergoing gene editing interventions should be made fully aware of the potential risks prior
to receiving the treatment, and their informed consent should be obtained prior to the
procedure. Given that the off-target effects can now be sensitively and comprehensively
quantified, 18 patients should be informed of the potential off-target risks, including the
probability and level of risk involved (from low to extremely high severity) during genetic
consultation.
6.10 HNGE has been postulated to advance medicine significantly given its potential to offer
novel methods of curing diseases, enhancing traits, conferring resistance, and treating
infertility. However, it is clear that the current state of the technology is largely in the
nascent stage that is lacking in both safety and efficacy data. Therefore, the risks entailed
largely outweigh the benefits perceived from the use of gene editing technologies, which
compromise on the principle of proportionality. With the current understanding of gene
editing tools, it is difficult to ascertain that future generations of individuals receiving the
treatment would be free of harm, which places the principles of sustainability and solidarity
into question. Nonetheless, research in HNGE have continued to improve the precision of
gene editing technologies to ensure responsible stewardship of science.
17
Katti, A. et al. (2023). Generation of precision preclinical cancer models using regulated in vivo base
editing. Nature Biotechnology. doi:10.1038/s41587-023-01900-x.
18
Park, S.H. et al. (2022). Comprehensive analysis and accurate quantification of unintended large gene
modifications induced by CRISPR-Cas9 gene editing. Science Advances, 8(42). doi:10.1126/sciadv.abo7676.
62
CHAPTER 7: SAFETY AND LONG-TERM EFFECTS OF HNGE
7.1 Gene editing offers new ways of treating diseases and may potentially be used for
enhancement of human performance. However, gene editing has yet to receive unequivocal
acceptance for widespread use in the clinic. This is because the technology is still in its early
development, which raises concerns regarding the safety and unknown long-term side
effects of the technology on individuals receiving the treatment. This chapter discusses the
ethical principles of proportionality, sustainability, and responsible stewardship of science,
the ethical issues of long-term side effects and consequences of non-heritable and heritable
gene editing, and recommendations to manage these consequences.
Issue 1: Possibility of long-term repercussions following non-heritable gene

editing
7.2 Since the development of CRISPR as a tool for gene editing, several therapeutics involving
this technology are currently being evaluated in non-heritable gene editing clinical trials and
approved for use. 1 ,3 Notable ones that have been granted the Regenerative Medicine
Advanced Therapy (RMAT) designation by the FDA for accelerated approval include, inter
alia, exagamglogene autotemcel (exa-cel) for sickle cell disease (SCD) and transfusion-
dependent beta thalassaemia (TDT).2 This same treatment was approved by the UK and is
sold under the brand name ‘Casgevy’, and is meant to prevent episodes of excruciating pain
that are typical of sickle cell disease and free people with beta thalassaemia from regular
blood transfusions.3 Another treatment that is granted accelerated approval by the FDA is
CRISPR-modified chimeric antigen receptor T (CAR-T) cells that targets cancer cells for
leukaemia and lymphoma, bringing hope to afflicted patients who otherwise do not have
effective treatment options.
7.3 While clinical trials for non-heritable gene editing may lead to the development of new
solutions to treat complex genetic diseases in the future, the long-term safety and stability
of non-heritable gene editing remain to be sufficiently addressed even in preclinical studies.4
As such, unforeseeable repercussions could arise years after patients received treatment
from non-heritable gene editing clinical trials and may result in undesirable biological
consequences or side effects. For instance, off-target modifications resulting from the
treatment of gene editing could trigger activation of cancer-causing genes and affect the
1
Henderson, H. (2023). CRISPR clinical trials: A 2023 update. Innovative Genomics Institute (IGI).
https://innovativegenomics.org/news/crispr-clinical-trials-2023/ Retrieved on 17 November 2023.
2
Vertex Pharmaceuticals (2023). Vertex and CRISPR therapeutics complete submission of rolling biologics
license applications (Blas) to the US FDA for exa-Cel for the treatment of sickle cell disease and transfusion-
dependent beta thalassaemia. https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-
therapeutics-complete-submission-rolling Retrieved on 17 November 2023.
3
Emily, M. (2023). First CRISPR drug: UK approves Casgevy to prevent pain from sickle cell disease and beta
thalassaemia. https://geneticliteracyproject.org/2023/11/20/first-crispr-drug-uk-approves-casgevy-to-prevent-
pain-from-sickle-cell-disease-and-beta-thalassaemia/. Retrieved on 21 November 2023.
4
Doudna, J.A. (2020). The promise and challenge of therapeutic genome editing, Nature, 578(7794), pp. 229–
236. doi:10.1038/s41586-020-1978-5.
63
health of patients in the long term. 5 Therefore, researchers are advised to consider the
following ethical principles when conducting non-heritable gene editing for biomedical
research and clinical applications:
a. Proportionality
7.4 The principle of proportionality requires researchers to ensure the risks of HNGE
technologies are not disproportionate to its benefits, by minimising the harm to individuals
and future offspring while maximising benefits using non-heritable gene editing. While
clinical trials and clinical applications involving non-heritable gene editing can benefit
research participants and patients by allowing them to correct mutations that cause
underlying diseases, the potential harmful side effects and long-term consequences might
outweigh the benefits. Hence, principal investigators of HNGE clinical trials, as well as
clinicians providing treatment involving non-heritable gene editing, have to ensure that the
risks are not disproportionate to anticipated benefits, by maximising potential benefits while
maintaining a favourable risk-benefit ratio for clinical trial participants and patients.
b. Responsible stewardship of science
researchers to be prudent about the resources utilised in the pursuit of HNGE research and
to consider the ethical guidelines governing applications of non-heritable gene editing.
Given the largely unknown long-term effects of gene editing technologies, it would be
difficult to predict and avoid consequences that clinical trial patients may face in the future.6
Hence, conducting such clinical trials may expose patients to possible long-term
ramifications in the future despite gaining short term benefits. Appropriate measures, such
as establishing guidelines for evaluating off-target effects7 and risk assessments,8 should be
taken by researchers to anticipate and/or manage uncertainties and long-term consequences
associated with non-heritable gene editing to ensure responsible stewardship of science.
Patients should be fully informed of the risks and proper informed consent should be taken
prior to participating in clinical trials or receiving any treatment of non-heritable gene
editing.
7.6 Given that the long-term safety of non-heritable gene editing has not been fully established,
it is essential for researchers and physicians to conduct long-term follow-up on patients and
participants of clinical trials evaluating new therapeutic modalities for non-heritable gene
editing. This would help to mitigate the risk of any delayed adverse event occurring due to
5
Teboul, L. et al. (2020) ‘Variability in genome editing outcomes: Challenges for research reproducibility and
clinical safety’, Molecular Therapy, 28(6), pp. 1422–1431. doi:10.1016/j.ymthe.2020.03.015.
6
The Swedish National Council on Medical Ethics (2022) Editing of the Human Genome: Summary of a report
from the Swedish National Council on Medical Ethics. Available at: https://smer.se/wp-
content/uploads/2022/04/smer-2022_1_english_summary_webb.pdf. Retrieved on 17 November 2023.
7
Ishii, T. (2016). Somatic Genome Editing for Health: Disease Treatments and Beyond. Curr Stem Cell Rep 2,
313–320. https://doi.org/10.1007/s40778-016-0061-5.
8
Bittlinger, M. et al. (2022). Risk assessment in gene therapy and somatic genome-editing: An expert interview
study. Gene and Genome Editing, 3–4, p. 100011. doi:10.1016/j.ggedit.2022.100011.
64
the treatment.9 For instance, four out of nine patients successfully treated in a clinical study
investigating the use of gene therapy for severe combined immunodeficiency (SCID) were
found to develop leukaemia up to 68 months after gene therapy.10 In addition, the FDA
updated the guidelines in 2020 on the design of long-term follow-up studies for the
collection of data on delayed adverse events following the administration of a gene therapy
product. This suggests that studies using gene-editing products should follow up with
patients for at least 15 years, and highlights the importance of long-term follow-up. 11
Nonetheless, it should be noted that such long-term monitoring of patients after the trial
poses the following ethical challenges:
i. Experimental approaches commonly employed in clinical trials such as

randomised controlled trials are usually not suitable for long-term
monitoring. 12 This is because subjects randomly assigned to a particular
treatment regimen for prolonged periods (e.g., five or more years) or to a
placebo group may choose to opt out of the study in the event a better treatment
becomes available, or may decide to switch therapy for other reasons such as
poor prognosis or treatment-related side effects.13
ii. The use of placebo may become less ethical and relevant for trials with
increased study durations, especially in situations where patients with
dilapidating conditions, such as cardiovascular diseases or cancer, are placed
in the placebo control group.14 Clinical trials carried over a longer duration
also necessitates an open label study design where both researchers and
participants are aware of the treatment being administered. Otherwise,
researchers may conduct an uncontrolled trial (without a placebo group), with
all participants receiving the same treatment if there is no standard of care, and
might reap results that are insufficient to establish efficacy of the
intervention.12 Nonetheless, an open label study or an uncontrolled trial may
be considered more ethical compared to the use of placebo, as patients are not
denied any treatment which may prevent or delay death or other major
consequences from the disease.
iii. As the duration of a study increases, the number of research subjects in the
study may decline further. It was reported that in four participants drop out on
average, citing reasons such as fear of side effects, study procedures,
9
Meredith, L. (2022). Long-term follow-up studies: Gene therapy products, protocols and potential issues.
https://www.Precisionformedicine.com/blogs/long-term-follow-up-studies-gene-therapy-products-protocols-
potential-issues/. Retrieved on 21 November 2023.
10
Hacein-Bey-Abina, S. et al. (2008). Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy
of SCID-X1. Journal of Clinical Investigation, 118(9), pp. 3132–3142. doi:10.1172/jci35700.
11
(2021). Gene therapy needs a long-term approach. Nature Medicine, 27, 563. Doi:10.1038/s41591-021-01333-
6.
12
Herbert, R.D., Kasza, J. and Bø, K. (2018) Analysis of randomised trials with long-term follow-up, BMC
Medical Research Methodology, 18(1). doi:10.1186/s12874-018-0499-5.
13
Morden, J.P. et al. (2011). Assessing methods for dealing with treatment switching in randomised controlled
trials: a simulation study. BMC Med Res Methodol 11, 4. https://doi.org/10.1186/1471-2288-11-4
14
Ellenberg, S.S. (2003). Scientific and ethical issues in the use of placebo and active controls in clinical
trials. Journal of Bone and Mineral Research, 18(6), pp. 1121–1124. doi:10.1359/jbmr.2003.18.6.1121.
65
inconvenient location and lack of support from family.15 This may result in
missing or incomplete data due to participants not completing the study (i.e.,
loss of follow-up), undermining the reliability and validity of efficacy studies
for the non-heritable gene editing treatment.
Issue 2: Difficulty in predicting how the gene alterations as a result of heritable

gene editing interact with genetic variants and the environment, and the
subsequent side effects
7.7 Compared to non-heritable gene editing, clinical applications of heritable gene editing raise
significantly more concern pertaining to the safety and long-term consequences of its use.16
While heritable gene editing may prove to be useful in eradicating genetic diseases
especially in children at birth by precisely correcting the genetic sequence, there is a
likelihood of creating permanent unintended changes that could be passed down to future
generations. Such modifications made to the genome may invoke unprecedented biological
consequences, including disrupting inherent protection from infection as well as activation
of genes with harmful effects.17
7.8 Mutations introduced to genes may interact with inherent gene variants present within an
individual and effect unprecedented biological outcomes. 18 Inherent gene variants are
changes in a person’s DNA sequence which exist prior to gene editing and can be inherited
or non-inherited. Inherited variants, also called germline variants, are passed down from
parent to child and are present throughout a person’s life. Non-inherited variants occur at
some point during a person’s life and may occur during natural cellular processes such as
cell division, or due to environmental factors such as exposure to ultraviolet radiation from
the sun or smoking. 19 While heritable gene editing can present prospective parents the
opportunity to have a biological child without passing on a genetically-heritable disease, the
current technology still lacks the ability to predict how these exogenous genetic alterations
may interact with existing gene variants within the child. The difficulty in anticipating and
in turn, mitigating possible side effects arising from the intrinsic genetic interaction as well
as that with the environment could expose the future offspring to lethal long-term
ramifications. Furthermore, the lack of studies on the side effects of gene editing on intrinsic
gene-gene interaction and the environment suggests the unpredictability of the long-term
consequences.
7.9 The inability to predict the undesirable outcomes and consequences of heritable gene editing
could be attributed to the fact that control experiments are only performed on a small group
15
Poongothai, S. et al. (2023). Strategies for participant retention in Long Term Clinical Trials: A participant –
centric approaches. Perspectives in Clinical Research, 14(1), p. 3. doi:10.4103/picr.picr_161_21.
16
Almeida, M. and Ranisch, R. (2022). Beyond safety: Mapping the ethical debate on Heritable genome editing
interventions. Humanities and Social Sciences Communications, 9(1). doi:10.1057/s41599-022-01147-y.
17
Rubeis, G. and Steger, F. (2018). Risks and benefits of human germline genome editing: An ethical
analysis. Asian Bioethics Review, 10(2), pp. 133–141. doi:10.1007/s41649-018-0056-x.
18
Mani, R. et al. (2008). Defining genetic interaction. Proceedings of the National Academy of Sciences, 105(9),
pp. 3461–3466. doi:10.1073/pnas.0712255105.
19
NHS England Genomics Education Programme. (2022). Constitutional (germline) vs somatic (tumour) variants.
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/constitutional-germline-vs-somatic-
tumour-variants/. (Retrieved on 10 November 2023).
66
of cells.20 The current ability to perform quality control experiments on only a subset of
cells means that the precise effects of genetic modification to an embryo may be impossible
to predict until after the child is born.6 In some cases, potential problems and side effects
may not surface for years even after the child is born, making it difficult to predict the side
effects of heritable gene editing. Wei and Nielsen reported in their study in 2019 that
CCR5Δ32 homozygote carriers in the UK Biobank were shown to suffer from 21% increase
in their mortality rate. The CCR5 gene has been widely demonstrated to be involved in the
human immune system. While the loss of its function may be protective against diseases
such as multiple sclerosis, spontaneous hepatitis C viral clearance, chronic and aggressive
periodontitis as well as confer resistance against HIV-1 infection,21 the authors of this study
postulated that the Δ32 mutation could be highly pleiotropic and likely increase
susceptibility of an individual with the mutation to develop other common diseases.
7.10 Given the above considerations, researchers are advised to consider the following ethical
principles when conducting heritable gene editing for clinical applications (if permitted):
a. Responsible stewardship of science
7.11 The principle of responsible stewardship of science requires researchers to be committed to

ensuring that scientific knowledge, data, processes, and know-how of gene editing
technologies are put to good use to improve health outcomes, and to acknowledge the
difficulties and uncertainties along with the benefits of heritable gene editing for clinical
applications (if permitted in the future). Researchers also have the obligation to minimise
potential risks to individuals and their future offspring associated with gene editing
intervention. With the current lack of long-term safety and efficacy data of the gene editing
technologies, the use of heritable gene editing is currently deemed unsafe for future
offspring with long term implications where possible exposure to serious side effects may
be fatal for the future offspring. The use of heritable gene editing can only be considered
safe for clinical applications following further research studies to prove the safety and
efficacy of gene editing technologies.
b. Sustainability
7.12 The principle of sustainability provides that research and applications of HNGE should
ensure that adverse effects or harm rendered from gene editing technologies are not passed
down to future generations. Given that the long-term consequences of the heritable gene
editing cannot be predicted or mitigated until the birth of the modified child, any of its
clinical applications would infringe the principle of sustainability as the welfare of the
offspring and future generations are likely compromised when exposed to serious side
effects.
20
Lanphier, E. et al. (2015). Don’t edit the human germ line, Nature, 519(7544), pp. 410–411.
doi:10.1038/519410a.
21
Li, T. and Shen, X. (2019). Pleiotropy complicates human gene editing: CCR5Δ32 and beyond, Frontiers in
Genetics, 10. doi:10.3389/fgene.2019.00669.
67
7.13 Intergenerational monitoring, which refers to long-term follow-up studies of research
participants and their descendants, could help researchers to determine the long-term side
effects of heritable gene editing on the individual that may be passed on to future
generations, and assess its safety and efficacy for clinical use. 22 One example of
intergenerational monitoring in biomedical research would be the Framingham Heart Study
examining the natural history, risk factors, and prognosis of cardiovascular, lung, and other
diseases. The study began recruitment of research subjects in 1948, and enrolled the second
and third generation of the original subjects in 1971 and 2002 respectively. The follow-up
studies included clinical and laboratory assessments of cardiac structure and function. 23
However, intergenerational monitoring in clinical trials, like other procedures in biomedical
research, poses the primary ethical challenge with respect to a person’s right to autonomy
and privacy:
a. Personal and medical information of subjects involved in intergenerational monitoring

have to be collected with appropriate consent of the participants. 24 However, the
descendants of a child conceived from an edited embryo in a clinical trial may invoke
a limited waiver of privacy during occasions requiring management of risks associated
with heritable gene editing and communication of any adverse findings with subjects
on whom intergenerational monitoring is carried out.22 The waiver could apply to
certain key aspects of the child’s life as well as its descendants, which could raise
difficult issues involving informed consent. The reason being that parents are unable
to provide consent that binds their children past the legal age when the children can
exercise their own judgement and decide whether to continue as participants of the
study as this would violate their autonomy.22
7.14 In view of the above ethical consideration, patients could opt for PGD as an alternative
procedure instead of heritable gene editing for clinical applications (if permitted) to ensure
their children do not inherit their genetic conditions. While not a curative therapy, PGD
could ensure that future offspring are not affected by the genetic condition by evaluating
embryos for specific genetic conditions (see chapter 5 for the alternatives to HNGE).
Consideration: Issue 2 may not be applicable to embryos that would not have existed
if gene editing was not performed/embryos that were affected by genetic mutations that
lead to catastrophic conditions. The risk of possible side effects may not outweigh the
risks involved when the embryos do not undergo gene editing, and therefore heritable
gene editing may be attempted for such cases, if permitted.
22
Cwik, B. (2019). Intergenerational monitoring in clinical trials of germline gene editing. Journal of Medical
Ethics, 46(3), pp. 183–187. doi:10.1136/medethics-2019-105620.
23
Splansky G. L., et al. (2007). The Third Generation Cohort of the National Heart, Lung, and Blood Institute’s
Framingham Heart Study: design, recruitment, and initial examination. American Journal of Epidemiology,
165(11), 1328-35. doi:10.1093/aje/kwm021.
24
Ranisch, R., Trettenbach, K. and Arnason, G. (2022). Initial heritable genome editing: Mapping a responsible
pathway from basic research to the Clinic. Medicine, Health Care and Philosophy, 26(1), pp. 21–35.
doi:10.1007/s11019-022-10115-x.
68
Issue 3: Lack of sufficient safety and efficacy data for the use of heritable gene
editing for infertility
7.15 Heritable gene editing presents as a possible infertility treatment for individuals with
fertility issues through unravelling of underlying genetic causes25 as well as modifying the
genes associated with infertility in germ cells.26 For example, CRISPR-Cas9 technology is
used to identify and study potential infertility mutations, by modelling infertility-causing
mutations in mice and evaluating whether the human mutation renders the mice infertile.
For example, researchers have been using the CRISPR-Cas9 system to produce mice that
lack testis-specific genes, and studies have revealed that several genes are indispensable for
male fecundity.27 However, preclinical studies have yet to establish the safety of these gene
editing technologies in mammalian models and humans, apart from rats.28 Hence, heritable
gene editing is still considered to be unsafe for clinical use to treat male/female infertility
as they can be exposed to unwanted side effects such as mutagenesis.29 For example, while
studies have shown that gene therapy involving viral vectors could correct spermatogenesis
in infertile mice, there are major concerns pertaining to translating these studies to clinical
applications, such as insertional mutagenesis, cell-specific targeting, and pronounced
inflammation.29
a. Proportionality
7.16 The principle of proportionality requires researchers to ensure risks of heritable gene editing
for infertility are not disproportionate to its benefits by minimising the harm to individuals
and future offspring. Given the lack of safety data on current gene editing technologies for
treatment of infertility in humans, clinical applications could harm the individuals
undergoing the treatment and might outweigh the benefits of helping prospective parents
conceive. Infertile couples are recommended to address their fertility problems through
other safer alternatives, such as medicines, surgical procedures and assisted reproduction
technology such as IVF procedures until the efficacy of gene editing for infertility is well
established (see chapter 5 for the alternatives to HNGE).
7.17 Hence, while non-heritable and heritable gene editing hold tremendous promise for
addressing genetic disorders and advancing medical science, the long-term safety and
efficacy remain a paramount concern. The safety and ethical issues necessitate a cautious
and well-regulated approach to ensure the responsible application of gene editing
technologies until these concerns are addressed in the future. Rigorous research, ongoing
25
Singh, P., & Schimenti, J. C. (2015). The genetics of human infertility by functional interrogation of SNPs in
mice. Proceedings of the National Academy of Sciences, 112(33), 10401-10436. doi:10.1073/pnas.1506974112
26
Hall, S.S. (2016). The first tinkering with human heredity may happen in the infertility clinic. Scientific
American. Available at: https://www.scientificamerican.com/article/the-first-tinkering-with-human-heredity-
may-happen-in-the-infertility-clinic1/. Retrieved on 17 November 2023.
27
Soojin, P, Keisuke, S, et. al. (2020). CRISPR/Cas9-mediated genome-edited mice reveal 10 testis-enriched
genes are dispensable for male fecundity. Biology of Reproduction, 103(2), pp 195 to 204.
doi:10.1093/biolre/ioaa084.
28
Chapman, K.M. et al. (2015). Targeted germline modifications in rats using CRISPR/Cas9 and spermatogonial
stem cells. Cell Reports, 10(11), pp. 1828–1835. doi:10.1016/j.celrep.2015.02.040.
29
Pathak, S., Sarangi, P. and Jayandharan, G.R. (2022). Gene therapy for female infertility: A farfetched dream
or reality? Cell Reports Medicine, 3(5), p. 100641. doi:10.1016/j.xcrm.2022.100641.
69
monitoring, and clear ethical guidelines are imperative to mitigate risks and uphold the
wellbeing of individuals. It would also be important to consider the potential benefits from
the advancements in HNGE and risks as well as ethical considerations to ensure the long-
term safety and efficacy of the technology.
70
CHAPTER 8: PROCUREMENT AND USE OF HUMAN EMBRYOS AND OOCYTES
IN HNGE RESEARCH
8.1 Human embryos have been used by researchers on gene editing as a tool to enhance
knowledge about human gene function and early embryonic development, as well as to
advance research on infertility, genetic diseases, and intractable diseases. In 2015, the first
case of gene editing in early-stage human embryos was reported in China, where CRISPR
was employed to edit the human beta-globin gene associated with beta-thalassaemia. 1
However, the use of embryos in gene editing research raises several ethical issues. This
chapter provides an overview on the 14-day limit for embryo research, the different types
of embryos used in HNGE research, and discusses the ethical issues involved in the
procurement and use of embryos and oocytes in gene editing research, the application of
relevant ethical principles of respect for persons, justice, proportionality, and transparency,
and recommendations to manage the ethical issues.
A. The 14-day rule
8.2 The BAC, in its ‘Ethics Guidelines for Human Biomedical Research (2021 revised edition)’,
recommends against developing human embryos for research after the 14th day.2
8.3 The 14-day rule was first proposed by the Ethics Advisory Board of the US Department of
Health, Education, and Welfare and later endorsed by the Warnock committee in the UK 3.
It is used in science policy and regulation to limit research, including gene editing research,
on human embryos to a maximum period of 14 days after their creation or to the equivalent
stage of development that is normally attributed to a 14-day-old embryo4. The placing of
the boundary at 14-days originated because the primitive streak appears after the 14th day
of human embryo development, signalling the onset of cell differentiation and growth of
organs including the nervous system. This rule has been highly influential and adopted by
many countries to facilitate ethical research on embryos.
8.4 While it was not possible to culture human embryos in-vitro for 14 days at the time when
the rule was implemented, with scientific advancement, maintaining physiologically normal
embryos in culture beyond 14 days is becoming a foreseeable reality5. Hence, there has been
continuing pressure to modify the rule. For example, many UK scientists are calling for the
current 14-day limit on embryo research to be doubled to 28-days, so that they can study the
1
Liang, P. et al. (2015). CRISPR/Cas9-mediated gene editing in human Tripronuclear zygotes. Protein &
Cell, 6(5), pp. 363–372. doi:10.1007/s13238-015-0153-5.
2
Ethics guidelines for human biomedical research (2021 revised) (2021). Bioethics Advisory Committee
Singapore. https://www.bioethics-singapore.gov.sg/publications/reports/bac-ethics-guidelines-2021/. Retrieved
on 8 December 2023.
3
Insoo, H, Amy, W, and Josephine, J. (2016). Embryology policy: Revisit the 14-day rule. Nature 533, pp. 169
– 171. doi:10.1038/533169a.
4
John, B, and Annelien, L. (2018). Should the 14-day rule for embryo research become the 28-day rule? EMBO
Molecular Medicine, 10:e9437. doi:10.15252/emmm.201809437.
5
Embryo Research (2021). Culturing human embryos beyond 14 days: a call for public debate.
https://www.focusonreproduction.eu/article/News-in-Reproduction-Embryo-research. Retrieved on 7 November
2023.
71
unexplored areas of early human development. This could yield major scientific
breakthroughs for infertility, miscarriage, and birth defects.6
8.5 However, given that culturing embryos for up to 14 days only became possible in 2016,
research into embryos between seven to 14 days is still in the early stages7. In addition, most
discoveries to date have been within the first seven days, where researchers have been using
gene editing technologies to reveal the role of key genes in human embryos in the first few
days of development8. Hence, it might be premature to consider an extension of the 14-day
limit. Therefore, the BAC’s position on this issue remains unchanged even for gene editing
research.
B. Different types of embryos used in research
8.6 The different types of embryos used in gene editing research can be distinguished based on
their source:
a. surplus embryos left over from clinical IVF procedures where couples could choose
to save the embryos for subsequent cycles in the treatment or donate them to research
or other couples with fertility difficulties;9
b. embryos created specifically for the purpose of research using gametes procured
specifically for research studying specific gene mutations or profiles.
8.7 The BAC in its ‘Ethics Guidelines for Human Biomedical Research 2021’ recommended
that the creation of human embryos solely for research purposes in Singapore can be
justified only when there is strong scientific merit and potential benefit from such research.2
However, the Human Biomedical Research (Restricted Research) Regulations 2017 only
allows surplus embryos created in assisted reproduction treatment to be used for biomedical
research, following approval from the IRB 10 . This effectively prohibits the creation of
embryos for research purposes even when there is strong scientific merit and potential
benefit. Hence, there may be a need for the regulatory authority to review current regulations
for restricted research to enable further advancements in biomedical research, including
gene editing research.
8.8 With regard to the use of oocytes or embryos in biomedical research, the BAC’s position is
that specific and personal consent from the donors must be obtained before any oocyte or
6
Michelle, R. (2023). Scientists: Allow forbidden 28-day embryo experiments. BBC News.
https://www.bbc.co.uk/news/health-67204553. Retrieved on 2 November 2023.
7
Bruce, P., and Daniel, R. (2021). Why we should not extend the 14-day rule.
https://pubmed.ncbi.nlm.nih.gov/34112721/. Retrieved on 24 January 2024.
8
The Francis Crick Institute. (2017). Genome editing reveals role of gene important for human embryo
development. https://www.crick.ac.uk/news/2017-09-20-genome-editing-reveals-role-of-gene-important-for-
human-embryo-development. Retrieved on 24 January 2024.
9
Machado, C.S. (2020). The fate of surplus embryos: Ethical and emotional impacts on assisted
reproduction. JBRA Assisted Reproduction. doi:10.5935/1518-0557.20200015.
10
Human Biomedical Research (Restricted Research) Regulations 2017 (2017).
https://sso.agc.gov.sg/SL/HBRA2015-S622-2017. Retrieved on 8 December 2023.
72
embryo is used for research. The potential donors should be provided with sufficient
information and time to make an informed decision.2 In particular, consent for donation of
surplus oocytes or embryos should be kept separate from the consent of treatment for women
undergoing fertility treatments. The researcher seeking consent for the donation of eggs and
embryos for research should not be the physician administering the fertility treatment.2 The
BAC also asserts that women who intend to donate eggs specifically for research (i.e., those
who are not undergoing fertility treatment) must be interviewed by an independent panel
given that the process of donating eggs for research is time-consuming, invasive, and
associated with a certain degree of discomfort and risk. The panel must be satisfied that the
women are of sound mind, understand the nature and consequences of the donation, and
have freely given explicit consent, without any inducement, coercion, or undue influence.2
8.9 While surplus embryos from IVF are commonly used by researchers in various countries
for gene editing research, there may be limited availability of gametes with desired
genotypes or genetic profiles.11 If a scientist becomes interested to study gene mutations in
oocytes for a given disease-causing gene, or to correct a specific gene mutation, it is
essential to obtain oocytes with the desired genotype. 12 For such oocyte gene editing
research, researchers may have to procure oocytes from women, which raises ethical issues
as described below.
Issue 1: Risks involved in procurement of human oocytes for HNGE research
8.10 The invasiveness of the medical procedures involved in procuring oocytes entails some risk
to donors. A woman has to undergo stimulation of her ovaries through multiple hormone
injections. Thereafter, the oocytes are collected under mild anaesthesia via special needle
attached to an ultrasound vaginal probe. Such ovarian stimulation carries some health risks,
as it can lead to ovarian hyperstimulation, a condition in which the ovaries become swollen
and painful because of receiving shots of fertility medicines to trigger ovulation. 13 The
condition may be life-threatening if severe, although such cases are rare.14 Such risk for
donors was observed in a study to correct a heterozygous MYBPC3 mutation, which causes
hypertrophic cardiomyopathy, in human preimplantation embryos using CRISPR-Cas9
editing. In the study, oocytes had to be procured from healthy donors, which were
subsequently fertilised by sperm carrying the mutation. The consent forms provided to these
healthy donors mentioned the risk of ‘death’ three times in the context of different
procedures, highlighting the significant risks of oocyte procurement in healthy donors.15
11
Emilia, N. & Heidi, C. (2020). Ethical issues related to research on genome editing in humans. Computational
and Structural Biotechnology Journal, 18, pp 887 – 896. doi:10.1016/j.csbj.2020.03.014.
12
Zhang, Y., Yin, T., Zhou, L. (2023). CRISPR/Cas9 technology: applications in oocytes and early embryos.
Journal of Translational Medicine, 21: 746. doi:10.1186/s12967-023-04610-9.
13
Mayo Clinic. (2024). In vitro fertilisation (IVF). https://www.mayoclinic.org/tests-procedires/in-vitro-
fertilization/about/pac-20384716. Retrieved on 1 March 2024.
14
Donation of Human Eggs for Research. (2008). Bioethics Advisory Committee Singapore.
https://www.bioethics-singapore.gov.sg/files/publications/reports/donation-of-human-eggs-for-research-full-
report. Retrieved on 24 January 2024.
15
Ma, H. et al. (2017). Correction of a pathogenic gene mutation in human embryos. Nature, 548(7668), pp. 413–
419. doi:10.1038/nature23305.
73
Other potential risks could also be psychological in nature, including anxiety, mood swings,
and post-donation adjustment.16
8.11 With the scarcity of human embryos and gametes, particularly oocytes that are available for
biomedical research, this generates various concerns. These concerns would include the risk
of exploitation through commercialisation of eggs as an unintended consequence of
substantial compensation amounting to an inducement,14 which could risk undermining the
autonomy of the donors (e.g. such as to take undue risks against their better judgment).17
Healthy women who volunteer to donate oocytes specifically for research incur loss of time
and earnings.14 However, in such cases, it would be difficult to determine a level of
compensation that will not amount to undue influence or inducement, as this would depend
on various factors, such as the financial status of the women concerned.14 Therefore, caution
must be taken to ensure that no one is exploited.
8.12 Given the above considerations, researchers are advised to consider the following ethical
principles when procuring oocytes for the purpose of HNGE research studying specific gene
mutations:
a. Respect for persons
8.13 The principle of respect for persons maintains that individuals participating in HNGE
research are respected as human beings and treated accordingly, including respecting their
rights to make their own decisions and ensuring that welfare and interests are protected. It
is important for women to be fully informed of the risks involved and given sufficient time
to express consent prior to undergoing oocyte procurement procedures for gene editing
research so that their autonomy is not impinged on. It is also important that there are
safeguards to protect oocyte donors and ensure that there is no coercion or undue influence
on their decision to donate. For example, Singapore’s Human Cloning and Other Prohibited
Practices Act 2004 prohibits the offering of valuable consideration for the supply of any
human egg, human sperm, or human embryo, 18 to avoid commodification of oocytes or
embryos, and to maintain donation as an altruistic act done without inducement. The Act,
however, allows for the reimbursement of any reasonable expenses incurred by a person in
relation to the supply of human egg, human sperm, or human embryo.
b. Justice
8.14 The principle of justice implies the need to fairly reciprocate individuals’ contribution to
HNGE research, and that researchers and their institutions shoulder some responsibility for
the welfare of participants in the event of adverse outcomes arising directly from their
16
National Academies Press. (2007). Assessing the Medical Risks of Human Oocyte Donation for Stem Cell
Research: Workshop Report. https://nap.nationalacademies.org/read/11832/chapter/3. Retrieved on 24 January
2024.
17
Rosario, M & Bartha, M. (2007). Monetary payments for the procurement of oocytes for stem cell research: In
search of ethical and political consistency. Stem Cell Research, 1(1). Pp 37 – 44. doi: 10.1016/j.scr.2007.09.003.
18
Singapore Human Cloning and Other Prohibited Practices Act. (2004).
https://sso.agc.gov.sg/Act/HCOPPA2004. Retrieved on 8 December 2023.
74
participation in HNGE research. Based on this principle, the BAC, in its ‘Donation of
Human Eggs for Research’ advisory report, recommends that women should be
compensated for loss of time and earnings as a result of the procedures required to obtain
the eggs, only if the eggs were obtained specifically for research purposes, and not as a
result of clinical treatment.14 Such compensation should be in addition to any reimbursement
of expenses incurred, and should not be dependent on the quantity or the quality of the eggs
obtained, as it is not payment for the eggs.14 This also applies for gene editing research in
embryos or germline cells. Nonetheless, given that Singapore’s Human Cloning and Other
Prohibited Practices Act allows only for reimbursement of reasonable expenses incurred by
a person in relation to the supply of human gamete, and not compensation for loss of time
and earnings in particular, it is less clear as to whether compensation for loss of time and
earnings to donors are permitted and there should be more clarity provided by the relevant
regulatory authority on the stance. The relevant regulatory authority may also wish to
consider setting a limit on the amount of compensation to avoid any inducement. In the case
of donors who are not employed, the relevant regulatory authority should determine an
appropriate compensatory amount for these donors based on the time spent as a result of the
procedures required to obtain the eggs for research. The authority may need to review
current legislation to determine whether legislative amendments are required to implement
any proposal for compensation.14
8.15 In addition, the BAC, in its ‘Donation of Human Eggs for Research’ advisory report, also
recommends that egg donors should be provided with prompt and full medical care when
complications occur as a direct and proximate result of donating eggs specifically for
research.14 Given that the donation of eggs for research purposes is not a commercial
proposition, it is the responsibility of researchers and research institutions to provide the
medical care when required.14 This also applies for gene editing research in embryos or
germline cells.
c. Proportionality
8.16 The principle of proportionality requires researchers to ensure the risks of HNGE research
are not disproportionate to its benefits, by minimising the harm to individuals and future
offspring while maximising benefits gained from using gene editing. As oocyte procurement
could result in potential harm to the donor (even risk of death), it would be important for
researchers to weigh the benefits of procuring oocytes solely for gene editing research
against the risks such procurement could pose. Researchers should consider using surplus
embryos created through assisted reproduction treatment for HNGE research if the risks of
procuring oocytes solely for such research outweighs the benefits.
Issue 2: Risks involved in the use of human embryos for HNGE research
A. Risk of invalid consent and privacy breach as a result of genome sequencing
8.17 Genome sequencing of embryonic cells is conducted to verify whether an embryo has been
edited in the desired way and to assess for off-target effects.11 The entire genome of gamete
donors is also sequenced (i.e., from blood) to act as a reference sequence. During this
75
process, researchers may obtain genomic sequencing information from gamete donors, and
it might be possible that not all gamete donors are adequately informed of this aspect of
research and its implications.11 For example, the informed consent forms used in the study
on heterozygous MYBPC3 mentioned above did not explicitly mention about the genome
sequencing aspect of the research. Inadequate information and understanding of what
research participation entails undermines consent for research and may cause subsequent
withdrawal of consent and loss of trust, if donors find out that they have not been informed
of genomic sequencing. Genomic sequencing could also lead to a breach of privacy and
confidentiality of donors’ genomic data. For example, genomic sequencing can query nearly
all protein-coding regions of the human genome at once, including most genes believed to
have roles in disease. For researchers to glean meaning from these data, they must be
accompanied by phenotypic and demographic information. This increases the likelihood
that data may be linked back to individuals who contributed the data, even when de-
identified. Hence, breaching the confidentiality of donors’ genomic data. In addition,
researchers may share these data in biorepositories and databases, which may lead to
misuses of genetic information, that relate to risk of discrimination and social stigma.19
Therefore, researchers are advised to consider the following ethical principles when using
surplus embryos or oocytes procured from healthy individuals for gene editing research:
a. Transparency
8.18 The principle of transparency in HNGE research emphasises openness and clarity about the
research process, methods, and findings, which helps to ensure the credibility and
reproducibility of the study. It is important for researchers to ensure that donors of surplus
embryos or oocytes for gene editing research are fully informed of all aspects of the research
study, including any potential data that may be collected and their implications. This
transparency ensures valid consent and fosters trust and respect for donors’ autonomy in
HNGE research.
b. Respect for persons
8.19 The principle of respect for persons underlies the importance of protecting research
participants’ privacy and confidentiality of disclosed information to minimise harm to them.
Therefore, it is important for researchers to ensure that data obtained from genome
sequencing during gene editing research on human embryos are not misused, and ensure the
security of data storage, so that the privacy and confidentiality of embryo or gamete donors
are not breached.
8.20 The ethical considerations surrounding oocyte procurement and use of surplus embryos or
oocytes procured for biomedical research, including HNGE research, are intricate, raising
concerns related to potential harm to the donor and infringement of informed consent as
well as possible breach of privacy and confidentiality of donors’ genomic data. Balancing
potential scientific advancements offered by gene editing research with the ethical
19
Leila, J; Julie, C, et. Al. (2014). Research participants’ attitudes towards the confidentiality of genomic sequence
information. European Journal of Human Genetics, 22, pp. 964-968. doi:10.1038/ejhg.2013.276.
76
imperatives of informed consent and potential consequences are paramount, and this could
be achieved when researchers and research institutions prioritise respect for the autonomy
and well-being of oocyte donors, as well as ensure transparency in the research process.
77
CHAPTER 9: EQUITABLE ACCESS AND ALLOCATION OF RESOURCES
9.1 Technologies involving HNGE extend beyond discovering and developing therapies,
particularly for rare genetic disorders, severe diseases such as cancer and treatment of
infertility. These technologies can also be potentially used for enhancing specific traits.
However, as with many new modalities in medicine, gene editing technologies would give
rise to concerns of inequitable access by those who are in need but cannot afford them. This
affects particularly the low and middle income countries, where there is insufficient funding
and support for healthcare and high patient caseloads often hamper the timely delivery of
treatment options to patients. 1 At the same time, allocation of resources to further the
research and development of gene editing for clinical applications must be carefully
considered given that the technology remains in much debate pertaining to its ethical, legal
and social implications. 2 This chapter deliberates the potential issues arising from
inequitable access and allocation of resources in the use of HNGE in research and clinical
applications, as well as the ethical principles relevant to the issues.
Issue 1: Inaccessibility of HNGE technologies due to high costs
9.2 Therapies involving gene editing tools are costly due to the heavy investments by
pharmaceutical companies in research and development and market exclusivity granted by
patents.3 It is estimated that in 2016, gene therapies have an average cost of between USD
$1 to $2 million (approximately SGD $1.3 to $2.6 million) per dose.4 In 2022, the US Food
and Drug Administration (FDA) approved Hemgenix, the first gene therapy to treat
haemophilia B, a genetic disease that impairs blood clotting, which costs USD $3.5 million
(approximately SGD $4.6 million) per treatment, making it the most expensive drug in the
world.5 The high costs of cell and gene therapies are due to the complexity of producing,
handling, and controlling the cells or viral vectors required to make them, and is far more
complicated than working with the chemicals used to develop and produce traditional
pharmaceutical therapies.6 As monogenic diseases are rare, the treatments developed are
often targeted at a small pool of patients with such rare diseases, and the costs are set higher
to maximise return on investments for these companies. Nonetheless, it is possible that gene
editing interventions may be scaled up and made accessible to more people at affordable
1
Mohiuddin, A.K. (2019). Affordability issues of biotech drugs in low- and middle-income countries. Juniper
Online Journal of Public Health, 5(1). doi:10.19080/jojph.2019.05.555654.
2
Howard, H.C. et al. (2017). One small edit for humans, one giant edit for humankind? points and questions to
consider for a responsible way forward for gene editing in humans. European Journal of Human Genetics, 26(1),
pp. 1–11. doi:10.1038/s41431-017-0024-z.
3
Muigai, A.W. (2022). Expanding global access to genetic therapies. Nature Biotechnology, 40(1), pp. 20–21.
doi:10.1038/s41587-021-01191-0.
4
Marsden, G. et al. (2017). Gene Therapy: Understanding the science, assessing the evidence, and paying for
value. Institute for Clinical and Economic Review. Report from the 2016 ICER Membership Policy Summit.
https://icer.org/assessment/gene-therapy-2016/. Retrieved on 8 December 2023.
5
Naddaf, M. (2022). Researchers welcome $3.5-million haemophilia gene therapy — but questions remain.
Nature. https://www.nature.com/articles/d41586-022-04327-7. Retrieved on 8 December 2023.
6
Genetic Engineering & Biotechnology News. (2023). Cell and Gene Therapy Manufacturing Costs Limiting
Access. https://www.genengnews.com/insights/cell-and-gene-therapy-manufacturing-costs-limiting-access/.
Retrieved on 8 December 2023.
78
costs in the longer term as these technologies advance and become increasingly prevalent
following the availability of generics after the expiry of patents.3 In addition, the Rare
Disease Fund in Singapore has expanded in end 2023 to cover CTGTPs, which would help
to mitigate the high costs involved for patients.7 However, gaining equal access to HNGE
technologies-based gene therapies may still pose challenges for the economically
disadvantaged population. This results in health disparities due to inequalities in
socioeconomic status. Therefore, researchers and research institutions should consider the
following ethical principles when working on improving gene editing for use in research
and clinical applications:
a. Justice
individuals, which implies that access to the benefits of biomedical research involving
HNGE should be equitably shared in society. While therapeutic interventions employing
gene editing may subsequently become affordable with greater scale of production, the
current high cost of the technology may deny the less advantaged in the society access to
such medical treatments.8 This would further aggravate problems in healthcare equity since
the benefits of gene editing technologies would not be equally accessible to all and thereby
compromise the principle of justice.
b. Inclusivity
9.4 The principle of inclusivity maintains that benefits of research and clinical applications
involving HNGE are considered a public good and should be accessible to everyone within
the society. If medical treatments employing gene editing are costly, individuals with lower
socioeconomic status would not be able to access them despite their needs.9 As such, this
inequity in access to medicine may be conceived as differential treatment especially if those
that are denied access belong to minority populations, which would not be inclusive. In
March 2023, the organising committee for the Third International Summit on Human
Genome Editing argued that as interventions based on non-heritable gene editing become
more widespread, a global commitment to equitable, financially sustainable, and accessible
treatments becomes more urgent, and will require appropriate planning for costs and
infrastructural needs for gene therapy treatments.10 Currently, the European Union (EU) is
undergoing discussions to update its pharmaceuticals legislation, where one of the
objectives is to create a balanced system for pharmaceuticals in the EU that promotes
7
Ministry of Health (2023). Rare Disease Fund. https://www.moh.gov.sg/news-highlights/details/rare-disease-
fund. Retrieved on 9 February 2024.
8
Subica, A.M. (2023). CRISPR in Public Health: The Health Equity Implications and role of community in gene-
editing research and applications. American Journal of Public Health, 113(8), pp. 874–882.
doi:10.2105/ajph.2023.307315.
9
Hildebrandt, C. and Marron, J. (2018). Justice in CRISPR/cas9 research and clinical applications. AMA Journal
of Ethics, 20(9). doi:10.1001/amajethics.2018.826.
10
Byrne, J. (2023). Urgent action needed to reduce high costs of gene therapies. BioPharma Reporter.
https://www.biopharma-reporter.com/Article/2023/03/13/urgent-action-needed-to-reduce-high-costs-of-gene-
therapies. Retrieved on 8 December 2023.
79
affordability for health systems, including advanced therapy medicinal products (ATMPs),
while rewarding innovation.11
Issue 2: Under-representation of Asian population in clinical data involving

HNGE research
9.5 As with most novel therapeutics, any research activity or clinical application involving
HNGE would require clinical trial data for validation purposes. Participation in ongoing
research or clinical trials for gene editing could allow patients to receive experimental
interventions for a disease before it receives approval for human use.12 However, it was
perceived that more clinical trials were funded and conducted in the United States of
America, Europe and United Kingdom than in Asia. 13 This was observed in the low
participation of Asians in clinical trials, according to a 2020 analysis of global participation
in clinical trials conducted by the FDA.14 It was reported that out of 292,537 clinical trial
participants globally, 76% were white, 11% were Asians, and 7% were black. As such, this
may lead to insufficient representation or under-representation of Asian genomes and
phenotypes where population- or ethnicity- specific insights or trends relevant to the
comprehensive understanding of the gene editing intervention outcomes cannot be obtained.
For example, ethnicity and pharmacogenomics are inextricably linked, and drug responses
can vary based on the allele frequency present in different ethnic populations. 15 Some
populations may respond better to specific drugs that result in better clinical outcomes.
Therefore, design of clinical trials for HNGE research should consider the following
principles:
a. Justice
9.6 The principle of justice provides fairness and equality for all individuals, where benefits
harnessed from research and clinical applications of HNGE should be equitably shared in
society. Sufficient Asian representation in research or clinical trials for gene editing will
allow us to gain insights and extrapolate trends that are specific to the Asian population. If
there is insufficient representation of Asians, it may not be possible to garner insights
11
European Parliamentary Research Service (EPRS). (2023) Revision of the EU pharmaceutical legislation.
Initial Appraisal of a European Commission Impact Assessment.
https://www.europarl.europa.eu/RegData/etudes/BRIE/2023/747464/EPRS_BRI(2023)747464_EN.pdf.
Retrieved on 8 December 2023.
12
Hamzelou, J. (2023). More than 200 people have been treated with experimental CRISPR therapies. MIT
Technology Review. https://www.technologyreview.com/2023/03/10/1069619/more-than-200-people-treated-
with-experimental-crispr-therapies/. Retrieved on 8 December 2023.
13
Number of clinical trials by year, country, who region and Income Group (1999-2019) (Mar
2020) (2020) World Health Organization. https://www.who.int/observatories/global-observatory-on-health-
research-and-development/monitoring/number-of-clinical-trials-by-year-country-who-region-and-income-
group-mar-2020. Retrieved on 8 December 2023.
14
Sharma, A. and Palaniappan, L. (2021). Improving diversity in medical research. Nature Reviews Disease
Primers, 7(1). doi:10.1038/s41572-021-00316-8.
15
Patrinos, G. P., Quinones, L. A., Sukasem, C. (2023). Editorial: Pharmacogenomics and ethnicity: Prevalence
and clinical significance of pharmacogenomic biomarkers in indigenous and other populations. Frontiers in
Pharmacology, 14:1180487. doi: 10.3389/fphar.2023.1180487.
80
relevant to the Asian demographics to tailor customised healthcare for this population.16 As
a result, the population may not have equal access to or yield maximum benefits from the
technology or research, undermining the principle of justice.
b. Inclusivity
9.7 The principle of inclusivity maintains that research and applications involving HNGE should
be representative of population diversity and the benefits of such research should be globally
accessible. To encourage more Asian participation in clinical trials for gene editing
technologies, researchers can strengthen recruitment and engagement strategies to
communicate the benefits of participating in biomedical research. This is so that the
demographics of trial participants take into consideration the principle of inclusivity and
consider the various genomic profiles of a multi-ethnic society like Singapore. Researchers
should also improve access to information about clinical trials involving gene editing to
promote potential benefits of research. For example, in 2019, the World Health Organization
(WHO) Expert Advisory Committee on developing Global Standards for Governance and
Oversight of Human Genome Editing launched the Human Genome Editing (HGE)
Registry, which is a central database that collects information of clinical trials using human
gene editing technologies. In accordance with the principles of transparency and inclusivity,
the HGE registry aims at making information about clinical trials using gene editing
technologies easily accessible to all interested stakeholders, including the public.17
9.8 Developing new biotechnologies in unchartered grounds requires channelling of substantial

funds and resources into the domain. Given the early stage of the HNGE technology, careful
consideration to the eventual delivery of resultant therapies and prudent allocation of
resources should be established. This is so that equitable access to healthcare by the
population is ensured, following the principles of justice and inclusivity so that benefits
reaped from HNGE are available to all individuals regardless of socioeconomic status. At
the same time, clinical studies of experimental treatments employing HNGE should be
representative of the diversity of Singapore’s population. This would enable insights on
clinical outcomes relevant to the local demographics to be harnessed for use so that the
principles of justice and inclusivity are maintained.
16
Nguyen, H.-A.T. et al. (2021). Asians and Asian subgroups are underrepresented in medical research studies
published in high-impact generalist journals. Journal of Immigrant and Minority Health, 23(3), pp. 646–649.
doi:10.1007/s10903-021-01142-6.
17
World Health Organisation (WHO). Human Genome Editing (HGE) Registry.
https://www.who.int/groups/expert-advisory-committee-on-developing-global-standards-for-governance-and-
oversight-of-human-genome-editing/registry. Retrieved on 8 December 2023.
81
CHAPTER 10: GENETIC ENHANCEMENT AND THE EFFECTS ON SOCIETY
10.1 Gene editing is playing an increasing part in various therapeutic applications to treat and
prevent diseases. Recent advances have increased the possibility that gene editing can also
be used for purposes that go beyond therapies and medical interventions discussed in the
previous chapters. Such possible applications of gene editing technologies include genetic
enhancement in areas such as conferring resistance to diseases and enhancement of physical
attributes and cognitive abilities. This chapter discusses the ethical issues involved in
applications of gene editing technologies for genetic enhancement, and the application of
relevant ethical principles of proportionality, sustainability, justice, inclusivity,
transparency, and responsible stewardship of science.
10.2 Enhancing features of the human body is not an unfamiliar concept. 1 Biomedical
technologies, such as drugs and surgical techniques, are increasingly being used to combat
disease, and augment the capacities of normal and healthy individuals. The best-established
examples of enhancement are cosmetic surgery and doping in sports. In addition, some
drugs that are used to treat narcolepsy and attention deficit hyperactivity disorder have also
been shown to have small enhancing effects on attention and memory in normal
individuals.2 There are various drugs and different biomedical techniques that promise
dramatic effects. One such technique is the brain-machine interfacing, which some predict
may allow human brains to be connected directly to computers to improve our information
processing abilities.2 Given the incremental use and progress in scientific technology, many
forms of enhancements are broadly accepted by the society today and seen as efforts to
improve the lives of people with disabilities.1 While many of the current methods used for
physical, functional or mental enhancements only affect the individuals and not future
generations, this would not be the case if gene editing technologies are used for genetic
enhancements.
10.3 An international survey was conducted by Pew Research Center in 20 countries from
October 2019 to March 2020 across Europe, Russia, the Americas, and the Asia-Pacific on
the view towards specific circumstances where gene editing may be used.3 The survey was
conducted with representative samples of adults aged 18 years and older. In general, most
of the countries surveyed drew distinctions when it comes to specific applications of human
gene editing, including showing wide support for therapeutic uses.3 A demographically
representative sample of 1,501 people in Singapore, which included people of different
genders, ages, education backgrounds, and regions, found that although 29% of the people
responded that gene editing to change a baby’s genetic characteristics and make the baby
more intelligent would be appropriate, 62% responded that such applications would be
1
Masci, D. (2016). Human enhancement, Pew Research Center Science & Society.
https://www.pewresearch.org/science/2016/07/26/human-enhancement-the-scientific-and-ethical-dimensions-
of-striving-for-perfection/. Retrieved on 28 December 2023.
2
University of Oxford. (n.d.). Enhancement. https://www.practicalethics.ox.ac.uk/enhancement/. Retrieved on
16 May 2024.
3
Funk, C. et al. (2020). Biotechnology research viewed with caution globally, but most support gene editing for
babies to treat disease, Pew Research Center Science & Society.
https://www.pewresearch.org/science/2020/12/10/biotechnology-research-viewed-with-caution-globally-but-
most-support-gene-editing-for-babies-to-treat-disease/. Retrieved on 4 January 2024.
82
considered as a misuse of technology. While support for the notion was conceivably low, it
was still substantially greater than the median support level of 14% in other surveyed
countries.3 In the same survey, 68% of the people responded that it would be appropriate to
use gene editing to change a baby’s genetic characteristics to treat a serious disease or
conditions that the baby would have at birth, while 22% responded that such applications
would be considered as misuse of technology.3 As such, the local perspectives towards the
applications of gene editing technologies are largely supportive if they are used for
therapeutic purposes, but not for genetic enhancement.
10.4 The primary ethical concern with permitting heritable gene editing for the purpose of
enhancement is that heritable gene editing may affect future generations. This is because
any changes made to the genes of germline cells or embryos will be permanent and passed
down to future generations. Hence, future offsprings may be subject to any unintended
consequences or negative impacts that may arise as a result of genetic enhancement, which
might compromise their wellbeing (discussed in the later part of this chapter).
Issue 1: Risks of gene editing for enhancement are disproportionate to its benefits
10.5 Heritable gene editing, if permissible in future, will be employed in genetic enhancement
where germline cells or human embryos are genetically modified to acquire advantageous
features. 4 Although the perceived risks associated with gene editing technologies (e.g.,
unintended consequences) used for treatment of disease and enhancement of traits are
similar, these risks may be disproportionate to the benefits offered by gene editing for
enhancement purposes. For example, despite the risks involved, applications of gene editing
to treat or prevent serious genetic disorders and diseases may be more justifiable as there is
a clear medical need. However, risks involved in the applications of gene editing that goes
beyond addressing medical conditions, may be less justifiable when the goals are not
directly related to health improvement. Therefore, researchers, research institutions and
IRBs are advised to consider the following ethical principle for applications of gene editing
for enhancement if they are permitted in the future:
a. Proportionality
10.6 The principle of proportionality requires that risks of research and applications of gene
editing technologies are not disproportionate to their benefits by minimising the harm to
individuals and future offspring while maximising benefits. Gene editing for therapeutic
purposes often target well-understood genetic mutations, reducing the likelihood of
unintended consequences. In addition, severe illnesses caused by genetic disorders such as
blood cancers and lymphomas often lack effective treatment options, and gene editing
provides an alternative life-saving therapy. For such applications of gene editing, the risks
involved may be proportionate to their benefits. On the other hand, heritable gene editing
for genetic enhancement may involve manipulating multiple genes to achieve the desired
traits, and the intricate interplay of genes in complex traits makes it challenging to accurately
predict and control the outcomes.4 Genetic enhancement to confer resistance to diseases or
4
Cwik, B. (2019). Moving beyond “therapy” and “enhancement” in the ethics of gene editing. Cambridge
Quarterly of Healthcare Ethics, 28(04), pp. 695–707. doi:10.1017/s0963180119000641.
83
for enhancement of cognitive abilities, are often speculative and may be risky, especially
since enhancement is not intended for medical purposes and may be passed down to future
generations. Therefore, researchers are advised to weigh the benefits against the risks of
applications of gene editing for enhancement should they be permitted in the future.
Issue 2: Exacerbation of social inequity due to misuse of gene editing technologies

for enhancement
10.7 Given that gene editing technologies for prevention and treatment of serious or rare diseases
are currently available, it may not require significant innovation to performing intentional
alterations on the human genome for enhancement of physical or intellectual traits.5 While
heritable gene editing for the purpose of enhancement could help to select for desirable traits
by correcting natural biological variants, gene editing technologies may be misused and
abused for purpose of creating ‘designer babies’ by removing unwanted genes.6 To illustrate
this, gene editing technologies such as CRISPR may be used for cognitive enhancement
(e.g., increased memory), physical enhancement (e.g., change of eye colour), and athletic
enhancement (e.g., gene doping for greater performance). This could reinforce
discrimination between the genetically modified and unmodified individuals and exacerbate
social inequities.7 This may lead to the potential for establishing programs for design and
preferential reproduction of “more desirable” and “better” kinds of human beings which
borders on eugenics5. Therefore, researchers and research institutions are advised to
consider the following ethical principles when considering applications of gene editing for
enhancement if permitted in the future:
a. Justice
individuals and implies that access to the benefits of research and clinical applications
involving gene editing technologies should be equitably shared in society. The high costs of
gene editing would mean that only a small group of wealthy individuals may gain access to
technologies for the purpose of enhancement. 8 This could affect the distribution of
perceived advantages and disadvantages of genetic enhancement among people. As a result,
the selected or desirable traits would be concentrated within a privileged wealthy group and
could subject future generations to discrimination.6 This may exacerbate and reinforce
existing social division and inequality. Protecting the interests of future generations is
important, particularly those who are vulnerable to discrimination or social inequities like
individuals with disabilities or from lower-income backgrounds. This must be considered
as a collective and shared responsibility of both the research community and the public. If
permitted, the current generation’s decisions to use gene editing technologies to enhance the
traits of their future child could affect subsequent offspring. Given that applications of gene
5
Friedmann, T. (2019). Genetic therapies, human genetic enhancement, and … eugenics?, Gene Therapy, 26(9),
pp. 351–353. doi:10.1038/s41434-019-0088-1.
6
Sufian, S. and Garland-Thomson, R. (2021). The Dark Side of CRISPR, Scientific American.
https://www.scientificamerican.com/article/the-dark-side-of-crispr/. Retrieved on 15 January 2024.
7
Lau, P.L. (2023). Evolved eugenics and reinforcement of “othering”: Renewed Ethico-legal perspectives of
genome editing in reproduction, BioTech, 12(3), pp. 51. doi:10.3390/biotech12030051.
8
Muigai, A.W. (2022). Expanding global access to genetic therapies, Nature Biotechnology, 40(1), pp. 20–21.
doi:10.1038/s41587-021-01191-0.
84
editing technologies for enhancement could exacerbate social inequity, it may be necessary
to limit their uses to cases where they do not result in unfair advantage or disadvantage for
certain individuals, such as disease prevention, or improving quality of life by restoring
physical or cognitive abilities and functions. Other uses of gene editing technologies, such
as editing genes to enhance physical traits or cognitive abilities that could create unequal
opportunities in sports, education, or employment, and may need to be limited as they could
perpetuate existing social inequalities. Researchers, scientists and the society should also
develop a strong sense of stewardship of environmental, biological, and social factors to
ensure the well-being and interests of future generations are not compromised if such
applications of gene editing technologies are permitted in the future.
b. Inclusivity
10.9 The principle of inclusivity maintains that benefits of research and clinical applications
involving gene editing technologies are considered a public good and should be accessible
to everyone within the society. Gene editing technologies for genetic enhancement, if
permitted in the future, can promote inclusivity by providing individuals with the
opportunity to enhance traits such as intelligence, physical strength, or disease resistance,
hence reducing disparities that arise from natural genetic variations. This could lead to a
more inclusive society where everyone has access to means to improve themselves,
regardless of their initial genetic makeup. However, potential applications of gene editing
technologies for genetic enhancement could also create disparities among those who cannot
afford or access such enhancements. Therefore, it would be important to ensure equitable
access to these technologies for genetic enhancement to prevent widening existing
inequalities. If the use of gene editing technologies for genetic enhancement is permitted in
the future, research and governance frameworks should be established by research
institutions and relevant regulatory authorities to ensure such technologies are accessible to
the public. Researchers and scientists should ensure that the benefits of applications of gene
editing technologies for genetic enhancement are made available to everyone, to prevent
widening of social disparity.
10.10 In view of the potential discrimination that may arise from the use of gene editing
technologies for enhancement, initiatives or programmes to foster inclusion and support for
people who are vulnerable to discrimination (e.g., individuals with disabilities or
developmental needs) should be developed and implemented. Social inclusion can also be
promoted by eliminating discriminatory practices, educating the public and developing
inclusive workplace policies to provide equal opportunities. These policies may include
guidelines for improving communication with people with disabilities by taking into
consideration their disabilities, providing assistive devices, and allowing them to feel a
sense of belonging at the workplace. Social inclusion objectives such as improving the
ability, opportunity, and dignity of the disadvantaged on the basis of their identity should
also be put in place so as to engender an inclusive environment.
c. Transparency
10.11 The principle of transparency requires researchers and their institutions to report and
disseminate research methods, analysis, and data openly, clearly, comprehensively and in a
timely manner to ensure that results are reproducible and reliable, and to facilitate proper
interpretation and dissemination of findings by other researchers. Given that researchers
may not disclose research methods, analysis, and data for research studies that misuse gene
85
editing technologies for enhancement as accurately and openly as compared to when
researchers conduct gene editing research that is permitted, it would be important for
researchers, research institutions and approving authorities to ensure that reporting
mechanisms are in place to prevent misuse or abuse of gene editing technologies for
enhancement.
Issue 3: Shift in attitudes and behaviours towards reproductive choices
10.12 Heritable gene editing for enhancement purposes could lead to undesirable societal
expectations and change the perception of conventional reproductive choices among future
generations. This is because reproductive technologies offer a more certain way to select
the characteristics of the next generation than choice of reproductive partners. For example,
one study on Down’s syndrome screening in England and Wales concluded that although
the frequency of births of people with Down’s syndrome had not changed much over the
study period, the availability of prenatal screening and termination has had a significant
impact on the number of children who would otherwise have been born with the conditions
for which screening is available.9 With the availability of prenatal screening technologies,
parents now have the choice to selectively reproduce only healthy children (i.e., children
with no genetic diseases or conditions), and terminate pregnancies that are diagnosed with
severe genetic conditions. Heritable gene editing could represent a prospective reproductive
technology that would further increase the power and range of reproductive choice by
enabling prospective parents to have genetically related children while excluding or
including certain heritable characteristics (e.g., predisposition to certain diseases).9 If gene
editing technologies were to become more common and widely utilised, this could bring
into question the choices of people who refuse to use such technologies. A shift in
behaviours and expectations may affect the evaluation of the responsibilities of prospective
parents towards their future children. This could put pressure on prospective parents to have
children using gene editing technologies to secure commonly accepted conventional
outcomes.10 The choice of “desirable traits” that do not have a medical basis could be quite
subjective. Therefore, researchers and research institutions are advised to consider the
following ethical principles when considering applications of gene editing for enhancement
if permitted in the future:
a. Sustainability
10.13 The principle of sustainability provides that research and clinical applications involving
gene editing technologies should ensure that adverse effects or harm rendered by the use of
these technologies are not perpetuated to future generations. Given that applications of gene
editing technologies for enhancement could lead to the future generation facing
psychological distress to conform to society’s perception of ‘normal’ reproductive choices,
this could lead to compromising the future offspring’s welfare. Hence, such applications of
gene editing technologies may not be sustainable.
b. Responsible stewardship of science
9
Nuffield Council on Bioethics (2018). Genome editing and human reproduction: social and ethical issues.
https://www.nuffieldbioethics.org/publications/genome-editing-and-human-reproduction. Retrieved on 4 January
2024.
10
Nuffield Council on Bioethics (2018). Genome editing and human reproduction: social and ethical issues short
guide. https://www.nuffieldbioethics.org/assets/pdfs/Genome-editing-and-human-reproduction-short-guide.pdf.
86
researchers to consider the ethical guidelines governing applications of heritable gene
editing in the pursuit of biomedical research. Outcomes of biomedical research involving
gene editing technologies should always be aligned with society’s values and perceptions
to ensure responsible stewardship of science. However, since heritable gene editing for the
purpose of enhancement may result in a shift in social norms and behaviours towards
reproductive choices, any research or clinical trials involving the use of gene editing
technologies for enhancement may not be in alignment with society’s values and
perceptions as they may lead to undesirable expectations that could harm the society.
Issue 4: Reduction of genetic diversity in human population
10.15 Heritable gene editing could contribute to the reduction or even elimination of some serious
inherited diseases from a population. However, variants associated with disease might also
be associated with other beneficial characteristics, which would also be lost.10 These
beneficial characteristics that are lost might be important for survival.6 For example, the
Chinese scientist, He Jiankui, disabled the C-C chemokine receptor 5 (CCR5) gene to confer
resistance to HIV in human embryos which resulted in the birth of twin girls. However, a
mouse experiment published in 2005 showed that CCR5 promotes trafficking of important
immune cells to the brain during the infection with West Nile Virus, and it was also found
that humans who lack this protein are more susceptible to severe encephalitis and even death
as compared to other people when infected with West Nile Virus.11 Therefore, the gene-
edited babies created as a result of He’s experiment may be resistant to HIV but may be
more susceptible to certain viral infections in the future. Hence, researchers and research
institutions are advised to consider the following ethical principles when considering
applications of gene editing for enhancement if permitted in the future:
a. Proportionality
10.16 The principle of proportionality requires that risks of research and clinical applications
involving gene editing technologies for enhancement are not disproportionate to their
benefits by minimising harm while maximising benefits to individuals and future offspring.
There is an obligation for researchers to reduce potential harm or limit to reasonable risks
to individuals and future offspring and maximise benefits as a result of gene editing
intervention. Applications of heritable gene editing to confer resistance to a particular
disease could unknowingly harm future offsprings by removing beneficial characteristics
associated with that disease which may be vital for survival. Hence, causing the potential
risks of such applications of gene editing (e.g., more susceptible to viral infections that may
be fatal) to be disproportionate to the potential benefits (i.e., to be resistant to a particular
disease).
10.17 Applications of gene editing technologies for genetic enhancement have potential benefits
of enhancing cognitive, physical, and functional abilities as well as increased resistance to
diseases. Nonetheless, such applications of gene editing technologies raise many ethical
implications and profound questions on fairness, societal norms, and unintended
consequences, which will require careful consideration. Therefore, applications of gene
11
Jon, C. (2019). Did CRISPR help – or harm – the first-ever gene-edited babies? Science.
https://www.science.org/content/article/did-crispr-help-or-harm-first-ever-gene-edited-babies. Retrieved on 2
January 2024.
87
editing technologies for genetic enhancement should only be considered after careful public
consultation and social debate, as well as when the safety and efficacy of such applications
have been well-established.
88
CHAPTER 11: GOVERNANCE AND FRAMEWORK TOOLS FOR HNGE
11.1 New and emerging technologies in biomedicine, such as HNGE, hold great potential in
improving human health.1 Gene editing tools such as CRISPR-Cas9 may be used to correct
aberrant genes and modify sequences within the human genome to treat genetic diseases,
improve fertility and enhance desirable traits. 2 However, the current state of HNGE
technology is still in its infancy, with many efficacy and safety concerns yet to be addressed.
Teething issues with the technology include off-target effects, unintended genetic changes
and genetic mosaicism, that could be passed down to future generations in cases such as
heritable gene editing for treatment of diseases or infertility.3 High costs of existing therapy
regimens involving HNGE may also limit the technology to only a small group of privileged
people and in doing so exacerbate social inequality.4 In the event gene editing for enhancing
specific traits is allowed, the move would also be detrimental to human population diversity
if genes for the same desirable traits are selectively altered.5
I. Governance Framework for HNGE Research
11.2 As with other technological advances, gene editing raises ethical and social issues that must
be addressed by having proper governance frameworks put in place. In 2021, the WHO
published a governance framework for HNGE derived from good practices on the
governance of emerging technologies.1 The recommended framework identifies values and
principles that justify the need for governance measures, and how the review or
strengthening of such measures may be carried out. It further sets out an assessment of the
tools, institutions, processes and considerations necessary for the successful implementation
of oversight and governance measures for HNGE. Proper governance is not limited to
legislative frameworks and regulations, but also includes other norms that may influence
the development of the technology at various levels.1 We elaborate on the governance and
framework tools for HNGE that should be put in place at the following respective levels:
a. Institutional research level: Institutional policies and Institutional Review Boards

(IRBs)
11.3 Policies and practices in place for HNGE research should be regularly reviewed by
institutions to manage risks and maximise potential benefits that may arise from such
research. Notably, the review should take into consideration the views of the public,
patients, or others with a vested interest in the activities conducted by such institutions. For
instance, a study carried out in Japan found that stakeholder involvement in the governance
of emerging medical technologies – for example, through collaboration between the
1
World Health Organization (2021). Human genome editing: A framework for governance, World Health
Organization. https://www.who.int/publications/i/item/9789240030060. Retrieved on 10 January 2024.
2
Furtado, R.N. (2019). Gene editing: the risks and benefits of modifying human DNA, Revista Bioética, 27(2),
pp. 223–233. doi:10.1590/1983-80422019272304.
3
Davies, B. (2019). The technical risks of human gene editing, Human Reproduction, 34(11), pp. 2104–2111.
doi:10.1093/humrep/dez162.
4
Subica, A.M. (2023). CRISPR in Public Health: The Health Equity Implications and role of community in gene-
editing research and applications, American Journal of Public Health, 113(8), pp. 874–882.
doi:10.2105/ajph.2023.307315.
5
Sufian, S. and Garland-Thomson, R. (2021). The Dark Side of CRISPR. Scientific American.
https://www.scientificamerican.com/article/the-dark-side-of-crispr/. Retrieved on 10 January 2024.
89
scientific research community and other parties (e.g., government bodies, experts, and
general public) within society – was critical to establishing an effective regulatory system.6
This is because perceptions on the use of HNGE may vary among individuals, and the
interests of a representative public should be examined in policy-making.
11.4 Institutions should ensure that all staff involved in HNGE research share responsibility and
accountability for the institution’s research being conducted according to appropriate
regulatory, ethical, and scientific standards within the levels of acceptable institutional risk.
For example, institutions in Singapore conducting any gene editing research on germline
cells or oocytes that falls within the scope of ‘restricted research’ under the Human
Biomedical Research (Restricted Research) Regulations 2017, should adhere to the
requirements of the Human Biomedical Research Act 2015 and seek the necessary approval
from the Ministry of Health prior to conduct of the research.7
11.5 In Singapore, IRB review is required when a research study is conducted at institutions or
partner institutions under the IRB’s purview (e.g., hospitals and polyclinics). IRB review is
also required if it involves human subjects and/or patients from that IRB or healthcare
cluster8, or is conducted by (or under the direction of) an employee under the purview of the
IRB or healthcare cluster. IRBs should ensure that the research is conducted to high ethical
standards, adheres to regulatory frameworks and that appropriate measures are taken to
protect the rights and welfare of human participants in HNGE research.9
b. Clinical level: Regulatory bodies, government and funding agencies, and standard
operating procedures (SOPs)
11.6 Regulatory bodies, government organisations and funding agencies10 that are developing
internal standard operating procedures (SOPs) for research and/or clinical trials on HNGE
should implement guidelines and put in place robust systems to understand, monitor, and
minimise or to mitigate the relevant risks and their impact on research subjects and patients
undergoing clinical trials. This may be done by considering the anticipated limitations of
the proposed technology and comparison with available standards for safety and efficacy
studies.1 An example would be the “Cellular & Gene Therapy Guidances” published by US
FDA for industry, FDA reviewers, and FDA staff.11
6
Aikyo, T., Kogetsu, A. and Kato, K. (2023). Stakeholder involvement in the governance of human genome
editing in Japan, Asian Bioethics Review, 15(4), pp. 431–455. doi:10.1007/s41649-023-00251-8.
7
Restricted research refers to any restricted human biomedical research as set out in Fourth Schedule of the
Human Biomedical Research Act 2015, including that involving human eggs and embryos.
https://sso.agc.gov.sg/Act/HBRA2015?ProvIds=Sc4-#Sc4-. Retrieved on 10 January 2024.
8
A healthcare cluster is an integrated system consisting of a range of healthcare institutions including acute and
community hospitals, primary care providers, nursing homes and other long term care providers, and medical
schools.
9
Bioethics Advisory Committee Singapore. (2004). Research involving human subjects: guidelines for IRBs.
https://www.bioethics-singapore.gov.sg/files/publications/reports/research-involving-human-subjects-guideline-
for-irbs-full-report.pdf. Retrieved on 10 January 2024.
10
Regulatory bodies, government organisations and funding agencies include the Health Sciences Authority of
Singapore (HSA), Agency for Science, Technology and Research (A*STAR), and the National Medical Research
Council (NMRC).
11
U.S. Food & Drug Administration. Cellular & Gene Therapy Guidances. Cellular & Gene Therapy Guidances
| FDA. Retrieved on 11 January 2024.
90
c. National level: Legislation and regulatory guidance
11.7 Governments and policy makers should ensure that laws and guidelines pertaining to the
application and research involving HNGE are constantly reviewed and revised. National
policies should be developed after careful review of the latest scientific evidence, and be in
alignment with prevailing societal values. Such reviews may be conducted by advisory
committees convened to examine safety concerns, sound practices and the scope of
allowable activities, to make recommendations for decision making.1 Stakeholder
consultations with the scientific community, patient advocates, and the general public
should be carried out with feedback sought, to ensure that policies properly take into
consideration the varied interests of differing stakeholders in society.
11.8 In this regard, a study assessing the national governance capacity of the development on
non-heritable gene editing technologies in eight geographically, socially, economically, and
culturally diverse countries, found that generally at the national level, the ministries of
health, science and technology play the lead role in deciding how governance mechanisms
(e.g., laws and regulations, codes of ethics, or research review processes) are framed and
responsibilities for biosafety and research ethics are allocated.12 The study also found that
there was a lack of clarity on the scope of the governance measures such as the
differentiation between non-heritable gene editing and heritable gene editing as well as
between research and treatment. Public consultation would be desirable to address the
shortcomings of inadequate information available, short timelines for responses, and the
lack of awareness from the public on the consultation processes. The study also found a lack
of information on enforcement or organisations that actively monitor for non-compliance,
which may suggest that while there are governance measures that exist in theory, the
practice may actually differ.
II. Tools and Approaches to Strengthen Existing Research Governance
11.9 Various approaches and tools, such as self-regulation by professional bodies, development
of guidelines, conduct of ethics and training courses, reinforcement of institutional
practices, establishment of HNGE registries and implementation of whistle-blowing
mechanisms, could be introduced to fortify existing research governance frameworks. We
turn to examine each of these below.
a. Professional self-regulation
11.10 Professional self-regulation within the scientific community can be an effective way to hold
scientists conducting HNGE research accountable to their peers, and functions as an
important deterrent to scientific misconduct. Professional self-regulation may rely on ethical
codes developed by advisory committees13 which may include representatives from patient
12
Millett, P. et al. (2023). Somatic Genome Editing Governance Approaches and Regulatory Capacity in Different
Countries. Social Science Research Network. http://dx.doi.org/10.2139/ssrn.4375726.
13
Conley, J. M., Davis, A. M., Henderson, G. E., Juengst, E. T., Meagher, K. M., Walker, R. L., Waltz, M., &
Cadigan, J. (2020). A New Governance Approach to Regulating Human Genome Editing. North Carolina journal
of law & technology, 22(2), pp. 107–141.
91
groups, public interest groups, advocacy organisations and civil society. Professional
societies can also develop professional guidelines for the sector, setting out best practices,
standards and ethical considerations in HNGE research. Such guidelines have the flexibility
to be reviewed regularly in response to the rapidly evolving field of gene editing
technologies, in contrast with legislative approaches.
11.11 However, professional self-regulation may give rise to potential conflicts of interest, 14 as
the party setting down guidelines or best practices may have certain self-interests in
pursuing the research or treatment. In addition, there might not be sufficiently rigorous
action taken against those who violate established standards because of professional
solidarity or other secondary interests, such as financial gain. For instance, conflicts of
interests in research or clinical practice may arise due to financial relationships between
researchers or medical professionals and entities such as biopharmaceutical or
biotechnology companies.
b. Providing education and training specific to HNGE for researchers and clinicians
11.12 Additional educational training or ethics modules specific to HNGE may be developed for
graduates who are looking to pursue research in gene editing or professions that may involve
clinical applications of gene editing.1 These modules could cover topics on research
integrity, ethics, the latest scientific developments in HNGE as well as various national
policies and guidelines relevant to the field. Providing training through public education,
engagement, empowerment of individual rights, and media communication will facilitate
better understanding and communication between researchers and the public.15 This would
in turn enable the scientific community to understand public concerns and needs, thereby
ensuring that information is conveyed accurately to prevent any distortion of public
perceptions and expectations about HNGE.
11.13 Institutions can fund or support educational or training programmes for their staff and IRB
members, so as to equip them with knowledge of gene editing technologies, developments
in HNGE research, appropriate ethical standards, national guidance documents and
advisories, as well as legislative updates.
c. Reinforcement of institutional practices
11.14 Institutions may review existing IRB ethics review processes and develop SOPs for HNGE
research. Institutions should also ensure that these SOPs are regularly revised and updated
to keep pace with the changes and developments in HNGE research, technologies, and
legislation.
14
Christian, A. (2022). Addressing conflicts of interest and conflicts of commitment in public advocacy and policy
making on CRISPR/Cas-based human genome editing, Frontiers in Research Metrics and Analytics.
doi:10.3389/frma.2022.775336.
15
World Health Organisation (2021). Human genome editing: recommendations.
https://apps.who.int/iris/bitstream/handle/10665/342486/9789240030381-eng.pdf?sequence=1. Retrieved on 10
January 2024.
92
11.15 In addition, annual reporting requirements, declaration mechanisms, processes for self-
monitoring of HNGE research may be put in place by institutions. These mechanisms may
also be used to keep track of achievements and other outcomes achieved from ongoing gene
editing research, including any advances in knowledge, as well as to report on any adverse
events arising from clinical trials.
11.16 Institutions may also review existing training programmes for IRBs to ensure members are
kept updated with the latest trends and developments of HNGE, and remain informed and
competent to review HNGE research applications. Institutions can also encourage greater
discussion amongst staff and researchers about ongoing HNGE research protocols and their
safeguards, in order to enhance understanding on how HNGE research should be conducted
to appropriate ethical standards.
d. Setting up HNGE registries
11.17 National registries tracking germline gene editing research on embryos and non-heritable
gene editing clinical trials can be set up to monitor all research and clinical trials involving
human gene editing. Such registries help enable information about HNGE research and
clinical trials to be made easily accessible to relevant stakeholders. For instance, the WHO
has set up a Human Genome Editing (HGE) Registry, which is a central global database that
assimilates information pertaining to clinical trials for human gene editing technologies.16
In accordance with the principles of transparency and inclusivity (refer to chapter 3 on the
definitions of ethical principles), the HGE Registry aims to allow information regarding
clinical trials on HNGE technologies to be made easily accessible to all interested
stakeholders such as researchers, medical professionals, and potential clinical trial
participants (i.e., patients). Failure to register any research that falls within the scope of the
HGE Registry may prevent appropriate oversight and valuable feedback from stakeholders,
which may amount to a violation of the principle of responsible stewardship of science,
transparency, and inclusivity.
(i) Germline gene editing research
11.18 In the wake of the CRISPR baby scandal, there is an urgent need to better regulate HNGE
research, and to ensure that any ongoing and subsequent germline gene editing research
activities are on a safe and sensible path. 17 Proposals for all ethically approved basic
research18 studies that employ gene editing tools in human embryos and gametes, including
those for evaluating treatment efficacy and safety, could be placed in an open registry.
Setting up a registry for germline gene editing research could encourage legitimate
16
World Health Organisation. Human genome editing registry, World Health Organization.
https://www.who.int/groups/expert-advisory-committee-on-developing-global-standards-for-governance-and-
oversight-of-human-genome-
editing/registry#:~:text=The%20Human%20Genome%20Editing%20(HGE,Trials%20Registry%20Platform%2
0(ICTRP). Retrieved on 10 January 2024.
17
Xue, Y. and Shang, L. (2022). Governance of heritable human gene editing world-wide and
beyond, International Journal of Environmental Research and Public Health, 19(11), pp. 6739.
doi:10.3390/ijerph19116739.
18
Basic research is a type of scientific research with the aim of improving scientific theories for better
understanding and prediction of natural or other phenomena.
93
submissions for fundamental and pre-clinical research and avoid abuse by businesses
seeking to prematurely commercialise gene editing technologies. Such registries could also
enable early recognition of any research that risks overstepping pre-defined boundaries, by
allowing researchers or interested stakeholders to flag up potentially dangerous germline
gene editing research. The set up of such registries for germline gene editing research should
involve a collaborative effort among scientific institutions, governmental bodies, regulatory
agencies, and ethicists.
(ii) Non-heritable gene editing clinical trials
11.19 For clinical trials involving non-heritable gene editing, well-established registries can
provide valuable information on treatment safety and the therapeutic efficacy of non-
heritable gene editing. This is applicable to HNGE where long-term monitoring may be
necessary to assess the safety and efficacy of the technology.19 Such non-heritable gene
editing clinical trial registries could help to prevent selective publication and reporting of
research outcomes, reduce unnecessary duplication of research effort, and enable access to
patients and the public on the available clinical trials that are planned or ongoing (to
facilitate decisions on participation).16 These registries could also provide an overview of
the landscape and data of existing research to ethics review boards that are considering
approval of new research studies of similar work or scope.
(iii) Non-heritable gene editing clinical applications
11.20 For treatments employing non-heritable gene editing technologies carried out under the
hospital exemption rule (i.e., innovation salvage therapy cases) but fall outside the scope of
clinical trials, data may not always be made publicly available. Setting up open-access
registries of such treatments could help facilitate access to treatment strategies and data,
provide evidence on the efficacy of treatments, and also help identify treatment-related costs
that may be considered for reimbursement.
e. Whistleblowing mechanisms
11.21 In addition to a registry to collect clinical trial data involving gene editing applications, the
WHO has also recommended whistleblowing mechanisms to be introduced 20 at an
institutional or national level. This is to establish effective reporting channels and to help
maintain comprehensive protection and support for those who report on illegal,
unregistered, unethical, or unsafe HNGE research.21
19
US Food and Drug Administration. Long term follow-up after administration of human gene therapy products.
2020. https://www.fda.gov/media/113768/download. Retrieved on 10 January 2024
20
Delaye, F. (2021). Genome editing: WHO banks on whistleblowers, Geneva Solutions.
https://genevasolutions.news/global-health/genome-editing-who-banks-on-whistleblowers. Retrieved on 11
January 2024.
21
Perrin, N. (2021). Enabling researchers to report concerns about human genome editing research: report for the
WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human
Genome Editing. https://apps.who.int/iris/bitstream/handle/10665/345331/WHO-SCI-RFH-2021.05-eng.pdf.
94
11.22 Research institutions can provide a well-advertised, safe, and confidential internal
mechanism for reporting allegations. To enable and encourage researchers or the public to
report concerns on unethical HNGE research from outside an institution, a new reporting
mechanism can be set up through the establishment of a confidential portal, website, or
hotline, which will allow individuals to report anytime and from anywhere. Follow-up
procedures should be put in place to investigate any information provided and to
demonstrate that action has been taken where appropriate.1 A two-stage investigation
process can be implemented, beginning with a preliminary enquiry to verify that the reported
concern is valid and not frivolous, followed by a more detailed rigorous investigation if
warranted. It would be important to establish the foregoing investigative and sanctioning
functions through national legislation, in consultation with the relevant research institutions
or funding agencies, with clear levers to address misconduct.
11.23 Protective mechanisms should be set up to mitigate potential harm that may result to
individuals (e.g., researcher or a member of the public) for reporting on unethical HNGE
research. Individuals reporting on such incidents should have their identities kept
confidential, and should be provided with the appropriate guidance and professional advice
throughout the reporting process.
f. International mechanism for reporting unethical germline gene editing experiments
11.24 In 2006, the WHO’s Expert Advisory Committee on Developing Global Standards for
Governance and Oversight of Human Genome Editing established an International Clinical
Trials Registry Platform (ICTRP) for clinical trials involving gene editing, through a World
Health Assembly resolution.16 While the ICTRP system can be leveraged on for reporting
unethical experiments, establishing a system supported by WHO may send a signal to the
world that reporting of unethical experiments is a responsibility of researchers globally.
III. Governance Framework for Heritable Gene Editing (for Treatment of Diseases,
Conferring Resistance, Enhancement of Traits, and Infertility) and Gene Editing in
Embryos or Germline Cells for Research Purposes
11.25 Heritable gene editing calls for greater attention in the establishment of proper governance
frameworks, since any genetic modifications made may be passed down to successive
generations. In particular, heritable gene editing for the treatment of diseases, conferring
resistance, enhancement of traits, and to treat infertility are deemed to pose greater risks to
future progeny due to the deleterious long-term health effects stemming from the
manipulation of germline cells or embryos.22 Furthermore, the clinical use of heritable gene
editing may exacerbate social implications such as inequity and undesirable social
expectations. In comparison, gene editing in embryos or germline cells for research
purposes is of lower risk, as research conducted on germ line cells do not affect future
generations. Therefore, the extent of oversight in developing governance and framework
tools should be corroborated with the extent of risks and sensitivity involved, whether for
22
Baylis, F. et al. (2020). Human Germline and heritable genome editing: The global policy landscape. The
CRISPR Journal, 3(5), pp. 365–377. doi:10.1089/crispr.2020.0082.
95
clinical applications of heritable gene editing or research activities for gene editing in
embryos or germline cells.
11.26 Due to the ethical issues involved in HNGE, as well as the potential for misuse and
downstream implications for patients and potentially their progeny, robust and
comprehensive governance frameworks will be critical in ensuring the safety and welfare
of patients undergoing such treatments or clinical trials. Institutions, professional bodies and
governments should collaborate to develop policies, guidelines and regulatory frameworks
that accord with prevailing societal values, minimising risks and maximising potential
healthcare benefits to the public.
96
CHAPTER 12: CONCLUSION
12.1 Applications of gene editing in human biomedical research have advanced developments in
genetics, disease modeling and therapeutics. The increasing use of gene editing in clinical
applications holds promise for treating genetic disorders, infertility, enhancing personalised
medicine and improving health outcomes. While these technologies have the potential to
confer resistance to diseases and enhancement of traits in the future, they may also bring
along unintended consequences and long-term effects on individuals and future generations.
Hence, it would be important to review the issues holistically and develop appropriate
recommendations to guide researchers, healthcare professionals and IRBs on the ethical use
of gene editing to ensure patient safety and welfare.
12.2 The BAC has conducted a comprehensive review of the ethical, legal, and social issues
arising from gene editing in human biomedical research and clinical applications, and
developed recommendations to guide the responsible use of such technologies. These
recommendations consider the ethical implications that may arise from such uses, and the
potential benefits and risks to individuals and future generations. The objectives of BAC’s
recommendations are not only to encourage more ethical debates on genetic enhancements
and discussions to address emerging ethical concerns involved in HNGE but to also
encourage and enable researchers to conduct HNGE research in an ethical manner. This
could also potentially lead to safer and more effective medical treatments for various genetic
disorders. The BAC’s recommendations on HNGE will shape policies to balance scientific
progress with ethical considerations and facilitate decision making.
12.3 In this advisory report, the BAC recommends that researchers, research institutions, IRBs,
and healthcare professionals consider the five substantive principles of (i) respect for
persons; (ii) solidarity; (iii) justice; (iv) proportionality; and (v) sustainability, as well as
the three governance principles of (i) inclusivity; (ii) transparency; and (iii) responsible
stewardship of science for HNGE research and clinical applications. BAC’s
recommendations for the safe and ethical use of gene editing technologies are summarised
as follows (refer to chapter 6 to chapter 10 for detailed discussion on these
recommendations):
a. Non-heritable gene editing (for research and clinical applications)
12.4 For any research and clinical application of non-heritable gene editing, the BAC
recommends that researchers, research institutions, and clinicians should ensure a
favourable risk-benefit ratio for patients undergoing clinical trials or clinical interventions
involving non-heritable gene editing. Patients must be informed of the potential risks and
possible complications and informed consent and IRB approval should be obtained prior to
the procedure.
12.5 Given that the long-term safety and efficacy of non-heritable gene editing are not fully
established, the BAC recommends that researchers, research institutions, and clinicians
should conduct long-term follow-up on patients of clinical trials involving non-heritable
gene editing. This is to mitigate the risk of any delayed adverse event occurring due to the
treatment. It would also be important for researchers and research institutions to take
97
appropriate measures, such as establishing guidelines for evaluating off-target effects and
risk assessments, to anticipate and manage uncertainties and long-term consequences
associated with non-heritable gene editing.
b. Gene editing on germline cells or embryos for research
12.6 The BAC does not recommend any gene editing research on human embryos after the 14th
day. Creation of human embryos solely for research purposes can only be justified when
there is strong scientific merit and potential benefit from such research. In future, if there is
stronger evidence of scientific merit for conducting gene editing research on human
embryos after the 14th day, the BAC may reconsider this position following public
consultation and stakeholder engagement. The BAC recommends that women donating
surplus embryos or undergoing oocyte procurement for any approved gene editing research
should be fully informed of all aspects of the research study by researchers and research
institutions. This includes the risks involved and any potential data that may be collected
and their implications. Donors should also be given sufficient time to express consent prior
to undergoing the procedures. The BAC also recommends that researchers and research
institutions take responsibility to ensure that data obtained from genome sequencing during
gene editing research on human embryos are not misused and safeguard the security of data
storage.
12.7 With regard to compensation of women undergoing oocyte procurement for gene editing
research, the BAC recommends that the relevant regulatory authority provide a clearer
stance on whether compensation for loss of time and earnings should be allowed, given that
the Singapore’s Human Cloning and Other Prohibited Services Act 2004 allows only for
reimbursement of reasonable expenses incurred by a person in relation to the supply of
human gamete. The BAC also recommends that the relevant regulatory authority consider
setting a limit on the amount of compensation to avoid any inducement.
c. Heritable gene editing for clinical applications

12.8 Clinical applications of heritable gene editing for (i) treatment of diseases; (ii) infertility;
(iii) conferring resistance to diseases; and (iv) enhancement of traits, have raised ethical and
safety concerns including unintended consequences, long-term effects, and other consent,
autonomy and inequality issues. The BAC does not recommend clinical applications of
heritable gene editing for any purpose in the near future, as there is insufficient evidence
from current research to ascertain that such applications of HNGE technologies are safe and
ethical. Hence, more research would need to be conducted to determine whether clinical
applications of heritable gene editing are considered safe and ethical before they can be
recommended in the future.
12.9 Nonetheless, if and when the risks involved in the applications of gene editing technologies
are sufficiently mitigated in the future, the BAC may then reconsider whether heritable gene
editing may be recommended for use as experimental intervention in certain situations to
prevent catastrophic conditions or for diseases where there are no other treatment options
available. Such situations may potentially benefit the future child where the benefits
involved may outweigh the risks. The experimental intervention involving heritable gene
98
editing must be conducted as a clinical trial with the appropriate approvals by ethics and
regulatory bodies. Given that the oversight of heritable gene editing is complex involving
ethical, scientific, and regulatory considerations, having a national review (i.e., input from
experts in genetics, bioethics, law, and various stakeholders such as policymakers, and the
public) for such experimental intervention would be important, to provide an additional
layer of oversight. This would enable a comprehensive evaluation from a broader
perspective, including potential societal impacts and international implications.
12.10 The governance of research and clinical applications of gene editing technologies is
important and serves to uphold ethical principles, foster responsible innovation and promote
ethical advancement of such technologies. The BAC’s recommendations aimed at
governing the ethical and responsible use of gene editing technologies are summarised as
follows (refer to chapter 11 on ‘Governance and Framework Tools for HNGE’ for detailed
discussion):
a. The BAC recommends that research institutions regularly review policies and practices
in place to manage risks and maximise potential benefits that may arise from HNGE
research. The BAC also recommends that IRBs should ensure that HNGE research is
conducted with high ethical standards, adheres to regulatory frameworks and that
appropriate measures are taken to protect the rights and welfare of human participants
in HNGE research.
b. The BAC recommends that regulatory bodies, government and funding agencies
encourage the implementation of guidelines and put in place robust systems to
understand, monitor, and minimise or to mitigate the risks and their impacts on research
subjects and patients undergoing HNGE clinical trials. This is carried out by also giving
due consideration to the anticipated limitations of gene editing technologies and
comparison with available standards for safety and efficacy studies.
c. The BAC recommends that governments and policy makers should constantly review
and revise legislations and guidelines pertaining to the application and research
involving HNGE. National policies should be developed after careful review of
scientific evidence and in alignment with societal values. The BAC also recommends
the conduct of stakeholder consultations with the scientific community and patient
advocates, and that feedback are sought from the general public so that policies
pertaining to HNGE are aligned with societal values.
d. The BAC recommends for different approaches and tools to be introduced to enhance
existing research governance frameworks for HNGE, such as self-regulation by
professional bodies, development of guidelines, conducting of ethics and training
courses, reinforcement of institutional practices, setting up of HNGE registries, and
implementing whistle-blowing mechanism.
e. With regard to heritable gene editing for clinical applications, the BAC recommends
that the extent of oversight in developing governance and framework tools should be
commensurate with the extent of risks and sensitivity involved for clinical applications
of heritable gene editing. Given that clinical applications of heritable gene editing for
(i) conferring resistance to diseases; and (ii) enhancement of traits pose more significant
99
ethical concerns as compared to clinical applications of heritable gene editing for
treatment of diseases or infertility, the BAC recommends that clinical applications of
heritable gene editing to confer resistance to diseases and to enhance traits should be
subject to a more stringent governance.
12.11 In addition to considering BAC’s recommendations on the governance of research and

clinical applications of HNGE as summarised earlier, it would be important to maintain
flexibility in the governance of HNGE, given that gene editing technology is a rapidly
evolving field. This would allow adaptation of scientific advancements with ethical
considerations and help foster responsiveness to emerging ethical challenges while ensuring
responsible and ethical use of ever advancing gene editing technologies. Achieving a
balance between flexibility and ethical oversight is crucial for navigating the complex
landscape of research and clinical applications of gene editing technologies. In short, the
governance of research and clinical applications of gene editing technologies should be
guided by the following considerations:
a. Guidance from international organisations
12.12 International organisations such as WHO develop guidelines and recommendations on a

regular basis (e.g., WHO’s framework for governance of human genome editing1). It would
be important to consider international organisations’ guidance on gene editing, and ensure
a consistent ethical framework and standards are adopted across borders which would help
promote global collaboration. This also prevents disparities in regulatory approaches,
fostering a unified stance on responsible gene editing. As the field of gene editing is
continuously evolving, BAC’s recommendations should keep abreast with the latest
international guidelines and recommendations, while tailoring them to fit the local context.
b. International governance and collaborations
12.13 International governance and collaborations on HNGE are important as they encourage for
research and clinical applications of gene editing to adhere to universally accepted
principles. Such collaborations can also promote responsible development through joint
research and sharing of best practices while promoting international ethical standards in
gene editing. 2 In addition, it would be important for policymakers and organisations
developing recommendations and guidelines pertaining to gene editing technologies to work
together with international institutions and bodies interested in the field of gene editing,
such as the WHO, International Bioethics Committee (IBC) of the United Nations
Educational, Scientific and Cultural Organization (UNESCO), and American Society of
Human Genetics, to discuss and share ethical issues arising from such technologies. Sharing
of information on laws and legislations relevant to gene editing, as well as engaging in
1
World Health Organization (2021). Human genome editing: A framework for governance.
https://www.who.int/publications/i/item/9789240030060. Retrieved on 17 January 2024.
2
Shampa, G; Soumya, G, et. al. (2023). Balancing potential benefits and ethical considerations of gene editing.
doi:10.1016/S0140-6736(23)01084-X.
100
collaborative international governance and oversight of gene editing, will enable better
alignment of ethical standards.
c. Continuous stakeholders and public engagement
12.14 Stakeholders and public engagement are and should continue to play an important part of
research and clinical applications of gene editing technologies and its advancement. These
engagements are crucial for ethical and transparent decision-making, and help to ensure
diverse perspectives are considered, and policies are shaped to align with broader societal
values. Through continuous engagement of the relevant stakeholders and the public, the
feedback obtained will allow policy makers, researchers, and healthcare professionals to
understand the public’s concerns and that HNGE progresses to serve the public’s interests.
d. Public education to raise awareness of the benefits and risks of HNGE applications
12.15 Public education plays a vital role in raising the public’s awareness of the benefits, risks,
and ethical issues involved in research and clinical applications of gene editing technologies,
and enhances the public’s knowledge on the latest developments in gene editing. Public
education also provides opportunities for the public to reflect and have discussions on
developments pertaining to gene editing technologies, and enables them to make informed
decisions about supporting or participating in gene editing research or in clinical trials
involving gene editing technologies. In addition, public education clarifies any
misperceptions regarding gene editing, and it equips individuals with the knowledge to
discern legitimate scientific advancements from potential misconceptions or fraudulent
activities. This reduces the likelihood of individuals’ participation in unethical or
questionable clinical trials involving gene editing technologies.
12.16 In conclusion, the ethical landscape surrounding gene editing requires academics,
researchers, healthcare professionals, IRBs, and research and healthcare institutions to
consider the ethical principles highlighted in this report when using gene editing
technologies for research or clinical applications. With further advancements in gene editing
technologies, it would be important to balance the potential benefits with the associated
risks, ethical and societal implications. Public education and continuous stakeholder
engagement are pivotal in fostering a responsible and ethical approach to gene editing.
Striking this balance will not only guide the scientific community but will also encourage
the broader public to remain informed and be actively involved in shaping the ethical
framework that governs the responsible use of gene editing technologies.
101
GLOSSARY
Alzheimer’s disease – A degenerative brain disorder that is common in the elderly,

characterised by progressive deterioration of mental functions leading to impaired cognition
and increased reliance on others for daily activities.
Amniocentesis – A procedure in which a small amount of the amniotic fluid surrounding the
foetus is withdrawn for testing for chromosomes and genetic disease.
Autologous (of cells or tissues) – Obtained from an individual’s own tissues, cells, or DNA.
Azoospermia – A medical condition where there is no measurable sperm in a man's ejaculate

(semen). Common causes include blockage or decreased sperm production by the testis.
Carrier – Someone who carries only one copy of a mutant gene in question. A carrier usually
shows no symptoms or very mild symptoms for the disease gene that he or she carries, as two
copies of the disease gene are required for a full-blown manifestation of the disease. A carrier
has the risk of transmitting the mutant gene to the next generation.
Chromosome – a threadlike structure of nucleic acids and protein found in the nucleus of most
living cells, carrying genetic information in the form of genes.
Clinical Ethics Committees (CECs) – Hospitals are required under the Healthcare Services
Act (HCSA) to set up CECs to advise clinicians on clinical ethical issues and also review other
specific ethical issues relating to care and management of patients in the healthcare institutions.
While CECs primarily play an advisory role, they also assume an adjudicatory role in specific
instances where the prescribed medical treatment involves complex ethical dilemmas.
Chorionic Villus Sampling (CVS) – A prenatal test that involves taking a sample of tissue
from the placenta to test for chromosomal abnormalities and other genetic problems.
Cystic fibrosis – Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the
lungs, digestive system and other organs in the body. It affects the cells that produce mucus,
sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people
with CF, a defective gene causes the secretions to become sticky and thick. Instead of acting
as lubricants, the secretions plug up tubes, ducts and passageways, especially in the lungs and
pancreas.
DNA – DNA, or deoxyribonucleic acid, is the molecule that carries genetic information for the
development and functioning of an organism. Each DNA is a linear molecule made up of
nucleotides or bases. There are four different types of bases in DNA and the order in which
these bases are arranged determines the protein to be formed. Each individual’s body contains
an identical set of DNA in nearly all of its cells. A great fraction of cellular DNA is located in
the cell nucleus (where it is called nuclear DNA), while the remaining can be found in the
mitochondria (where it is called mitochondrial DNA).
DNA methylation – An epigenetic mechanism that occurs by the addition of a methyl group
to DNA; this regulates gene expression by changing the activity of a DNA segment.
102
Epigenetics – The study of heritable changes in gene expression that are caused by factors
such as DNA methylation without a change in the DNA sequence itself.
Embryo – The initial stage of development of a multicellular organism. At 8 weeks of gestation,

the embryo becomes known as a foetus.
Extra-chromosomal DNA (abbreviated ecDNA) – Refers to any DNA that is found off
chromosomes, either inside or outside of the nucleus of a cell.
Foetal blood sampling (FBS) – A procedure to draw foetal blood from the umbilical cord of
the foetus during pregnancy.
Frameshift mutation – An insertion or deletion involving a number of base pairs that is not a
multiple of three. As the formation of proteins involves reading the RNA sequence in multiples
of three, this disrupts the reading frame and causes premature termination of translation.
Gamete – Sperm or egg cell.
Gene – A gene is the basic physical and functional unit of heredity. It is made up of DNA
which carries instructions to make molecules of RNA and proteins.
Gene therapy – Treatment of a genetic disorder by inserting functional genes to replace,

supplement, or manipulate the expression of nonfunctional or abnormal genes.
Genetic variant – An alteration in the most common DNA nucleotide sequence.
Genome – The complete set of DNA (genetic material) in an organism. The genome contains
the master blueprint for all cellular structures and activities for the lifetime of the cell or
organism. Found in every nucleus of a person's many trillions of cells, the human genome
consists of tightly coiled threads of DNA and associated protein molecules, organised into
structures called chromosomes.
Genotype – A specific set of alleles (variant forms of a gene) at particular position on the
chromosome.
Germ cell (Germline) – The cell (or cell line) from which sperm and egg (gametes) are derived.
Human immunodeficiency virus (HIV) – A virus that attacks the body's immune system. If
HIV is not treated, it can lead to AIDS (acquired immunodeficiency syndrome), a condition in
which there is progressive failure of the immune system.
Induced haematopoietic stem cells (iHSCs) – An adult somatic cell, such as a human skin
cell, that has been reprogrammed (or induced) into self-renewing stem cells capable of
replenishing all blood lineages.
Induced pluripotent stem cells (iPSCs) – An adult somatic cell, such as a human skin cell,
that has been reprogrammed (or induced) into an embryonic pluripotent state.
103
Institutional Review Board (IRB) – A committee that reviews for a proposed research study
to ensure adherence to relevant ethical, legal and institutional standards. Such boards are
designated to approve (or reject), monitor, and review biomedical and behavioral research
involving humans. For biomedical research, IRB approval is required by law before any
subjects can be recruited.
Intrauterine insemination – A procedure for treating infertility where sperm is placed directly
into the uterus using a small catheter.
In vitro fertilisation (IVF) – A clinical and laboratory procedure whereby the eggs and sperm
from a couple are extracted and fertilised outside their bodies. Such a procedure is a type of
assisted reproduction aimed at increasing the chances of a couple conceiving a baby.
Low-frequency mutation – Somatic mutation with allele frequency lower than 1% in an

individual's DNA.
Meiotic arrest – During the formation of oocytes in females, meiosis (cell division of germ
cells that produces the gametes) arrests twice. The first arrest occurs during prophase 1 in
embryogenesis and lasts until puberty. The second meiotic arrest occurs after ovulation during
metaphase 2.
microRNA (miRNAs) – A class of non-coding RNAs that play important roles in regulating
gene expression.
Monogenic diseases – Diseases caused by variation in a single gene and are typically
recognised by their striking familial inheritance patterns. Examples include sickle cell anemia,
cystic fibrosis, Huntington disease, and Duchenne muscular dystrophy.
Muscular dystrophy – Caused by changes (mutations) in the genes responsible for the
structure and functioning of a person’s muscles. These mutations cause changes in the muscle
fibers that interfere with the muscles’ ability to function. Overtime, this causes increasing
disability.
Mutation – A gene mutation is a permanent change in the DNA sequence that makes up a
gene. It ranges in size from one DNA base to a large segment of a chromosome. Gene mutations
can be inherited from a parent or acquired during a person’s lifetime. If a mutation occurs in
an egg or sperm cell during a person’s life, there is a chance that the person’s children will
inherit the mutation. Most mutations do not cause genetic disorders. For example, some
mutations alter a gene's DNA base sequence but do not change the function of the protein made
by the gene.
Missense mutations – Missense mutations occur when a single nucleotide base in a DNA
sequence is swapped for another one, resulting in a different amino acid being encoded at a
particular position in the resulting protein.
Mosaicism – A condition in which cells within the same person have a different genetic
makeup.
Off-target edits – Non-specific and unintended genetic modifications that occur at untargeted
sites in the genome that are genetically similar to the target site.
104
Oncogenesis – The process through which healthy cells become transformed into cancer cells.
Oocyte – An egg cell.
Percutaneous umbilical blood sampling (PUBS) – A test that takes foetal blood directly from
the umbilical cord.
Phenotype – The observable characteristics of the expression of a gene.
Pleiotropic – The phenomenon in which a single gene affects two or more apparently unrelated
phenotypic traits, resulting in multiple phenotypic expressions.
Polygenic disease – Disease caused by the joint contribution of a number of independently

acting or interacting genes. Examples include hypertension, coronary heart disease, and
diabetes.
Preimplantation genetic testing for aneuploidies (PGT-A) – A technique used to analyse

the number of chromosomes present in IVF embryos.
Preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) –

A test performed on embryo biopsies to screen embryos for chromosomal imbalances (extra or
missing chromosome material) resulting from a parental structural rearrangement.
Preimplantation genetic testing for monogenic gene defects (PGT-M) – A treatment which
involves checking the genes or chromosomes of embryos for a specific genetic condition.
Prenatal – During pregnancy and before birth.
Primitive streak – A transient structure whose formation, on day 15 of human development,

marks the start of gastrulation which is the early developmental process in which an embryo
transforms from a one-dimensional layer of epithelial cells (blastula) and reorganises into a
multi-layered and multi-dimensional structure called the gastrula.
Protein – Large and complex molecules of amino acid residues that play many critical roles in
the body. They do most of the work in cells and are required for the structure, function and
regulation of the body’s tissues and organs.
Retinitis pigmentosa (RP) – A group of rare eye diseases that affect the retina (the light-
sensitive layer of tissue in the back of the eye). RP makes cells in the retina break down slowly
over time, causing vision loss.
RNA – RNA, or ribonucleic acid, is a nucleic acid present in all living cells. Its principal role
is to act as a messenger carrying instructions from DNA for controlling the synthesis of proteins.
Severe Combined Immunodeficiency (SCID) syndrome – A group of rare disorders caused

by mutations in different genes involved in the development and function of infection-fighting
immune cells.
Sickle-cell anaemia – One of a group of inherited disorders known as sickle cell disease. It
affects the shape of red blood cells, which carry oxygen to all parts of the body.
105
Single nucleotide polymorphism (SNP) – A genomic variant at a single base position in the
DNA.
Somatic cell – All the body cells except the reproductive (germ) cells.
Somatic or adult stem cells – An unspecialised cell, present in a tissue or organ, that is able
to replicate itself and develop into specialised cell types of that tissue or organ, or into some
other cell types.
Spinal muscular atrophy (SMA) – A genetic disorder where cells of the spinal cord die,
resulting in progressively weaker muscles.
Spinocerebellar ataxia – A group of inherited brain disorders. It affects the cerebellum, a part
of the brain vital to coordination of physical movement, and sometimes the spinal cord. This
inherited condition worsens over time and causes specific problems with coordination, usually
affecting eyes, hands, legs and mobility, and speech.
Stem cell – An unspecialised cell that is able to replicate itself and develop into specialised
cell types (such as a red blood cell, nerve, or heart cell). Stem cells divide to form daughter
cells, in which some daughter cells differentiate into specialised cell types, and some daughter
cells retain the stem cell property to divide and make more new stem cells.
Spermatogonial stem cells (SSC) – Adult stem cells in the testis which continuously generate
daughter cells that differentiate into sperm cells. They keep their cellular pool constant through
self-renewal.
Thalassaemia – An inherited blood disorder caused when the body does not make enough of
a protein called haemoglobin, an important part of red blood cells.
106

Hnge Public Consultation Paper - VF

Uploaded by

Copyright:

Available Formats

Hnge Public Consultation Paper - VF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hnge Public Consultation Paper - VF

Uploaded by

Copyright:

Available Formats

ETHICAL, LEGAL, AND SOCIAL

ISSUES ARISING FROM HUMAN

BIOETHICS ADVISORY COMMITTEE

Emeritus Professor Roy Joseph

Associate Professor Lai Poh San

Associate Professor Lim Tit Meng

Professor Vineeta Sinha

Mr Tan Sze Yao

Dr Voo Teck Chuan

Professor Tan Sor Hoon (until June 2023)

Associate Professor Mahesh Choolani

Professor Julian Savulescu

Associate Professor Tan Meng How

Adjunct Associate Professor Tan Ee Shien

Professor Kazuto Kato

Adjunct Associate Professor (Dr) Raymond Chua Swee Boon

Dr Tiong Wei Wei

Mr Louis Peter Hor

Dr Durkeshwari Anbalagan-Raj (until Mar 2023)

Dr Phua Zheng Yen (Dec 2022 until Nov 2023)

Dr Chew Wei Leong

Professor Chin Jing Jih

Emeritus Professor Roy Joseph

Associate Professor Lai Poh San

Mr Charles Lim Aeng Cheng

Dr Nazirudin Bin Mohd Nasir

Associate Professor Ngiam Kee Yuan

Professor Vineeta Sinha

Professor Patrick Tan Boon Ooi

Mr Tan Sze Yao

Dr Voo Teck Chuan

In recent years advances in Human Nuclear Genome Editing (HNGE) technologies

Emeritus Professor Lee Eng Hin

b. Safety and Long-Term Effects of HNGE

c. Procurement and Use of Human Embryos and Oocytes in HNGE Research

d. Equitable Access and Allocation of Resources

5 Gene editing technologies extend beyond discovering and developing therapies,

e. Genetic Enhancement and the Effects on Society

f. Governance and Framework Tools for HNGE

The Executive Summary of recommendations

Human Nuclear Genome Editing (HNGE)

Advantages and Disadvantages of Non-Heritable Gene Editing, Heritable Gene Editing

a. Advantages and Disadvantages of Non-Heritable Gene Editing

b. Advantages and Disadvantages of Heritable Gene Editing for Clinical

c. Advantages and Disadvantages of Gene Editing in Embryos or Germline Cells for

Overview of Legislations and Regulatory Frameworks Governing HNGE

Objective of this Advisory Report

I. Local Legislation for HNGE

i. Non-Heritable Gene Editing (for research and clinical applications)

a. Human Biomedical Research Act 2015

b. Health Products Act 2007

c. Healthcare Services Act 2020 (HCSA 2020)

a. Human Cloning and Other Prohibited Practices Act 2004

b. Healthcare Services (Assisted Reproduction Service) Regulations 2023

c. Human Biomedical Research (Restricted Research) Regulations 2017

II. Overseas Legislation for HNGE

i. Non-Heritable Gene Editing (for research and clinical applications)

III. Comparison Between Local and Overseas Legislation for HNGE

a. Non-Heritable Gene Editing (for Research and Clinical Applications)