Presentation by Dr Steffi Friedrichs, AcumenIST, Human Germline Genome Editing, Marsilius Kolleg, Heidelberg University, 14. November 2018

The Debate on Human Germline
Genome Editing in the Context of
Evidence and Opinion

What to expect?
“An exact determination of the laws of heredity will probably
work more change in man’s outlook on the world, and in his
power over nature, than any other advance in natural knowledge
that can be foreseen.”
[William Bateson,“Problems of Heredity as a Subject for Horticultural Investigations”, 1900]
2Marsilius Kolleg Symposium: Human Germline Editing – Perspectives of global Regulation
14. November 2018, Heidelberg

Human Germline Genome Editing – WHY? (and why now?)
Three timelines
Induced / Controlled Mutations (Genome Editing)
Discussions / Meetings / Opinions
Heredity / Genetics / Genomics

Pythagoras:
likeness = spermism
Plato:
heredity theorem
Aristotle:
sperm& egg
(info > form > info > form …)
Darwin:
pangene
(pangenetics)
Mendel:
alleles as
information
Weismann:
"heredity tail"
Bateson (genetics):
genotype > phenotype
Galton:
phenotype > genotype
DNA & RNA are known
by the scientific
Griffith:
transmission without
Watson, Crick, Wilkins,
Franklin:
the structure of DNA
Berg & Jackson:
recombinant DNA
Jaenisch:
1st transgenic mouse
Sanger:
gene sequencing
Gentech:
biotechnology insulin
1st IVF child born
1st transgenesis in
gene therapy
human genome sequencing
Venter et al.:
first synthetic
bacterial genome
Permission (UK):
mitochondrial
Heredity, Genetics and Genomics – the Beginning

Heredity, Genetics and Genomics – the recent Past
Darwin:
pangene
(pangenetics)
Mendel:
alleles as
information
Weismann:
"heredity tail"
Bateson (genetics):
Galton:
DNA & RNA are known
by the scientific
Griffith:
Franklin:
Berg & Jackson:
recombinant DNA
Jaenisch:
Sanger:
gene sequencing
Gentech:
1st IVF child born
1st transgenesis in
gene therapy
Venter et al.:
first synthetic
bacterial genome
Permission (UK):
mitochondrial

Mutagenesis – from Observation to Control
Mutation by Radiation
Mutation by Chemicals
1st targeted Genome
Changes in yeast
1st targeted Genome
I-SceI (Meganuclease)
editing in yeast
ZFN in fruit flies
ZFN in vitro
ZFN in Zebrafish
ZFN in Rat
CRISPR/Cas-9 genome
editing agent
ZFN clinical trial (HIV)
CRISPR/Cas human
embryos editing (China)
start:TALEN Clinical Trial
(enhanced efficacy of CAR
T cells - cancer)
start: CRISPR/Cas
initial results from the
Mutation by Radiation
Mutation by Chemicals
1st targeted Genome
Changes in yeast
1st targeted Genome
I-SceI (Meganuclease) editing
in yeast
ZFN in fruit flies
ZFN in vitro
ZFN in Zebrafish
ZFN in Rat
CRISPR/Cas-9 genome editing
agent
ZFN clinical trial (HIV)
CRISPR/Cas human embryos
editing (China)
start:TALEN Clinical Trial
(enhanced efficacy of CAR T
cells - cancer)
start: CRISPR/Cas
Clinical Trial
initial results from the
1st clinical trial (ZNF)

Genetics and Genomics in the public Debate
International Eugenics
Conference
(London)
Buck vs Bell
Asilomar
Genetics & Public Policy Center (PEW) (USA):
"Human Germline Genetic Modification: Issues and
Options for Policymakers"
UNESCO:
"Report of the IBC on Updating Its
Reflection on the Human Genome and
Human Rights"
"1st International Summit on
Genome Editing"
(NAS et al.)
OECD:
"Gene editing in an international context: scientific,
economic and social issues across sectors"
Position Statement by the
American Society of Human
Genetics (ASHG)
ESHRE & ESHG:
"Responsible innovation in human
germline gene editing"
Nuffield Council on Bioethics
(UK)

Heredity, Genetics and Genomics – the recent Past
Darwin:
pangene
(pangenetics)
Mendel:
alleles as
information
Weismann:
"heredity tail"
Bateson (genetics):
Galton:
DNA & RNA are known
by the scientific
Griffith:
Franklin:
Berg & Jackson:
recombinant DNA
Jaenisch:
Sanger:
gene sequencing
Gentech:
1st IVF child born
1st transgenesis in
gene therapy
Venter et al.:
first synthetic
bacterial genome
Permission (UK):
mitochondrial

Genetics and Genomics in the public Debate
International Eugenics
Conference
(London)
Buck vs Bell
Asilomar
Genetics & Public Policy Center (PEW) (USA):
"Human Germline Genetic Modification: Issues and
Options for Policymakers"
UNESCO:
"Report of the IBC on Updating Its
Reflection on the Human Genome and
Human Rights"
"1st International Summit on
Genome Editing"
(NAS et al.)
OECD:
"Gene editing in an international context: scientific,
economic and social issues across sectors"
Position Statement by the
American Society of Human
Genetics (ASHG)
ESHRE & ESHG:
"Responsible innovation in human
germline gene editing"
Nuffield Council on Bioethics
(UK)

… and that’s why!

Research &
Understanding:
(controlled)
Mutagenesis
Research &
Understanding:
(controlled)
Mutagenesis
Research &
Understanding:
Heredity,
Genetics,
Genomics
Research &
Understanding:
Heredity,
Genetics,
Genomics
Public Debates
(& medical
Applications)
Public Debates
(& medical
Applications)
In the past 15 years:
Immense progress in understanding
and innovation in genomics and
controlled mutagenesis, and in the
(need for) public debates.

Not that long ago:
“Germline genetic modification is possible in animals, but not yet in
humans. If certain technical obstacles were overcome, human
germline genetic modification (HGGM) could allow human beings
to create permanent heritable genetic changes in their descendants
by changing the genetic makeup of human eggs or sperm, or human
embryos at the earliest stages.”
[Genetics and Public Policy Center (andThe Pew Charitable Trusts) (USA) ,“Human GermlineGenetic Modification: Issues and
Options for Policymakers”, 2005]
“Germline genetic modification is possible in animals, but not yet in
humans. If certain technical obstacles were overcome, human
germline genetic modification (HGGM) could allow human beings
to create permanent heritable genetic changes in their descendants
by changing the genetic makeup of human eggs or sperm, or human
embryos at the earliest stages.”
[Genetics and Public Policy Center (andThe Pew Charitable Trusts) (USA) ,“Human GermlineGenetic Modification: Issues and
Options for Policymakers”, 2005]

Research &
Understanding:
(controlled)
Mutagenesis
Research &
Understanding:
(controlled)
Mutagenesis
Research &
Understanding:
Heredity,
Genetics,
Genomics
Research &
Understanding:
Heredity,
Genetics,
Genomics
Public Debates
(& medical
Applications)
Public Debates
(& medical
Applications)

Human Genome Editing and the specific Case of the Germline
The genome editing of
the human germline (i.e.
oocyte, sperm, zygote, or
embryo) is a special case,
because it occurs in a
germ cell or embryo and
results in changes that
are theoretically present
in all cells of the embryo
and that could also
potentially be passed
from the modified
individual to offspring.
Strategies for genome
editing in human
reproduction
[Nuffield Council on Bioethics,“Genome editing and human reproduction”, July 2018]

A brief Overview of the applicable Regulation
xxxxxx
THE UNITED STATES does not allow the use of
federal funds to modify human embryos, but there
are no outright genome-editing bans. Clinical
development may require approval.
THE UNITED STATES does not allow the use of
federal funds to modify human embryos, but there
are no outright genome-editing bans. Clinical
development may require approval.
ARGENTINA bans
reproductive cloning, but
research applications of
human-genome editing
are not clearly regulated.
ARGENTINA bans
reproductive cloning, but
research applications of
human-genome editing
are not clearly regulated.
THE UNITED KINGDOM’s independent Human
Fertilisation and Embryology Authority may permit
human-genome editing for research, but the practice
is banned in the clinic.
THE UNITED KINGDOM’s independent Human
Fertilisation and Embryology Authority may permit
human-genome editing for research, but the practice
is banned in the clinic.
GERMANY has strict
laws on the use of
embryos in assisted
reproduction. It also
limits research on
human embryos, and
violations could result
in criminal charges.
GERMANY has strict
laws on the use of
embryos in assisted
reproduction. It also
limits research on
human embryos, and
violations could result
in criminal charges.
[adapted from:“The Landscape for Human Genome Editing”, Nature 526, 2015]
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
restrict the editing
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.
JAPAN, like China,
India and Ireland,
has unenforceable
guidelines that
of a human
embryo’s genome.

Perspectives of Human Germline Genome Editing - Research
"1st International Summit on Genome Editing" (NAS et al.), Dec. 2015
[The National Academies of Sciences, Engineering , Medicine,“Human Genome Editing: Science, Ethics, and Governance”, 2017]
In light of the technical and social concerns involved, the committee concluded
that heritable genome-editing research trials might be permitted, but only
following much more research aimed at meeting existing risk/benefit standards
for authorizing clinical trials and even then, only for compelling reasons and under
strict oversight. It would be essential for this research to be approached with
caution, and for it to proceed with broad public input.
In light of the technical and social concerns involved, the committee concluded
that heritable genome-editing research trials might be permitted, but only
following much more research aimed at meeting existing risk/benefit standards
for authorizing clinical trials and even then, only for compelling reasons and under
strict oversight. It would be essential for this research to be approached with
caution, and for it to proceed with broad public input.

Perspectives of Human Germline Genome Editing - Research
"1st International Summit on Genome Editing" (NAS et al.), Dec. 2015
[The National Academies of Sciences, Engineering , Medicine,“Human Genome Editing: Science, Ethics, and Governance”, 2017]
[…] particular, clinical trials using heritable genome editing should be permitted only if
done within a regulatory framework that includes the following criteria and structures:
• absence of reasonable alternatives;
• restriction to preventing a serious disease or condition;
[…]
• ongoing, rigorous oversight during clinical trials of the effects of the procedure on the
health and safety of the research participants;
• comprehensive plans for long-term, multigenerational follow-up that still respect
personal autonomy;
• maximum transparency consistent with patient privacy;
• continued reassessment of both health and societal benefits and risks, with broad
ongoing participation and input by the public; and
[…] particular, clinical trials using heritable genome editing should be permitted only if
done within a regulatory framework that includes the following criteria and structures:
• absence of reasonable alternatives;
• restriction to preventing a serious disease or condition;
[…]
• ongoing, rigorous oversight during clinical trials of the effects of the procedure on the
health and safety of the research participants;
• comprehensive plans for long-term, multigenerational follow-up that still respect
personal autonomy;
• maximum transparency consistent with patient privacy;
• continued reassessment of both health and societal benefits and risks, with broad
ongoing participation and input by the public; and

Perspectives of Human Germline Genome Editing - Application
Position statement by the American Society of Human Genetics (ASHG):
Based on an expert meeting (March 2015)
Endorsed by:
• UK Association of Genetic Nurses and Counsellors,
• Canadian Association of Genetic Counsellors,
• International Genetic Epidemiology Society,
• US National Society of Genetic Counselors,
• American Society for Reproductive Medicine
• Asia Pacific Society of Human Genetics, British Society for Genetic Medicine
• Human Genetics Society of Australasia
• Professional Society of Genetic Counselors in Asia, and
• Southern African Society for Human Genetics

(1) At this time, given the nature and number of unanswered scientific, ethical, and
policy questions, it is inappropriate to perform germline gene editing that
culminates in human pregnancy.
(2) Currently, there is no reason to prohibit in vitro germline genome editing on human
embryos and gametes, with appropriate oversight and consent from donors, to
facilitate research on the possible future clinical applications of gene editing.There
should be no prohibition on making public funds available to support this research.
(3) Future clinical application of human germline genome editing should not proceed
unless, at a minimum, there is
a) a compelling medical rationale,
b) an evidence base that supports its clinical use,
c) an ethical justification, and
d) a transparent public process to solicit and incorporate stakeholder input.
[Ormond et al.,“Human Germline Genome Editing”,The American Journal of Human Genetics 101, 167–176, 2017]

[Ormond et al.,“Human Germline Genome Editing”,The American Journal of Human Genetics 101, 167–176, 2017]

The Dichotomy of Human Germline Genome Editing
The ethical assessment of human germline genome editing falls, broadly, into two
categories:
1. those arising from its potential failure, and
2. those arising from its success.

Ethical Problems arising from its Failure
April 2015: Chinese Scientists genetically modify human embryos
86 embryos (i.e. non-viable IVF embryos):
- 71 survived
- 54 were genetically tested
- 28 had been successfully splices
“[…] the study is a landmark, as well as a cautionary tale.Their study should
be a stern warning to any practitioner who thinks the technology is ready for
testing to eradicate disease genes.“
[George Daley, stem-cell biologist at Harvard Medical School in Boston, USA]
"It underlines what we said before: we need to pause this research and make
sure we have a broad based discussion about which direction we’re going
here.“
“The ubiquitous access to and simplicity of creating CRISPRs creates
opportunities for scientists in any part of the world to do any kind of
experiments they want.”
[Edward Lanphier, President, Sangamo BioSciences in Richmond, USA]

… just one month before:
“At this early stage, scientists should agree not to modify the DNA
of human reproductive cells.
[…] But we cannot imagine a situation in which its use in human
embryos would offer a therapeutic benefit over existing and
developing methods.
[…] Established methods, such as standard prenatal genetic
diagnostics or in vitro fertilization (IVF) with the genetic profiling
of embryos before implantation, are much better options for
parents who both carry the same mutation for a disease.
[…] Many oppose germline modification on the grounds that
permitting even unambiguously therapeutic interventions could
start us down a path towards non-therapeutic genetic
enhancement.“
[“Don’t edit the human germ line”, Nature 519, 2015]
… and ethical Problems arising from its Success

These include:
• Missing consent of the “patient” (i.e. the child, for whom the parents decided)
 BUT: is the child really the only patient?
• Discrimination against “disabilities” (i.e. some patients do not wish to change their own medical condition, if
given the choice)
… and eventually:
• Economic/financial pressures to chose a single “fix” instead of a life-long treatment
Life-threatening
debilitating Disease
Life-threatening
Eugenics (positive & negative)
/ Enhancement
/ Enhancement

The question of Human Germline Genome Editing elevates the health-decision
of an individual to an issue of socio-political impact for society at large:
NOTE: for some, human germline genome editing may be more acceptable than approaches
that rely on pre-natal / -implant diagnostics followed by abortion / deselection.
Life-threatening
Life-threatening
/ Enhancement
/ Enhancement
Social Justice & equal
Access toTechnologies
Social Justice & equal
Access toTechnologies

Reality Check: ‘Life-threatening, debilitating Diseases’
• > 4000 genetic conditions … most are extremely rare
• < 200 orphan medicines, very few are curative or restore full health
• 80% of rare conditions have a proven single gene cause
• >99% of genetic conditions are rare: fewer than 5 in 10000 in the EU
[source: Genetic Alliance UK]
• > 4000 genetic conditions … most are extremely rare
• < 200 orphan medicines, very few are curative or restore full health
• 80% of rare conditions have a proven single gene cause
• >99% of genetic conditions are rare: fewer than 5 in 10000 in the EU
[source: Genetic Alliance UK]
Genome Editing holds significant potential to accelerate our progress towards meeting some of these needs:
• As a research tool, genome editing is accelerating our examination of the human genome’s relationship with rare
conditions
• As a somatic cell treatment, genome editing is a technique that is in the clinic, treating individuals affected by
rare conditions
• As a germline therapy, genome editing could deliver the option for couples to avoid having a child affected by
rare conditions
[Nick Meade, Director of Policy, Genetic Alliance UK, October 2018, EU Parliament]
Genome Editing holds significant potential to accelerate our progress towards meeting some of these needs:
• As a research tool, genome editing is accelerating our examination of the human genome’s relationship with rare
conditions
• As a somatic cell treatment, genome editing is a technique that is in the clinic, treating individuals affected by
rare conditions
• As a germline therapy, genome editing could deliver the option for couples to avoid having a child affected by
rare conditions
[Nick Meade, Director of Policy, Genetic Alliance UK, October 2018, EU Parliament]

… and that’s why we will be here for a bit longer
“Science advances one funeral at a time.”
[Max Planck, 1947 (incorrectly assigned)]

… and that’s why we will be here for a bit longer
“Science advances one funeral at a time.”
[Max Planck, 1947 (incorrectly assigned)]
“A new scientific truth does not triumph by convincing its
opponents and making them see the light, but rather
because its opponents eventually die, and a new generation
grows up that is familiar with it.”
[Max Planck, 1947]

Thank you!
Steffi Friedrichs
AcumenIST
W: www.AcumenIST.com
E: Steffi@AcumenIST.com
T: +32 496 07 57 85
Skype: SteffiFriedrichs
“A new scientific truth does not triumph by convincing its
opponents and making them see the light, but rather
because its opponents eventually die, and a new generation
grows up that is familiar with it.”
[Max Planck, 1947]

Presentation by Dr Steffi Friedrichs, AcumenIST, Human Germline Genome Editing, Marsilius Kolleg, Heidelberg University, 14. November 2018

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Presentation by Dr Steffi Friedrichs, AcumenIST, Human Germline Genome Editing, Marsilius Kolleg, Heidelberg University, 14. November 2018