Memorandum 34
Submission from the United Kingdom National
Stem Cell Network (UKNSCN)
The UKNSCN was established in November 2006
in direct response to Recommendation 10 of the Government's UK
Stem Cell Initiative report (the Pattison Report). It has been
set up primarily to promote the coordination of research at the
national level through promoting interdisciplinary collaboration
across the various sub-disciplines of stem cell research. In addition,
it will eventually become the national focal point for communication
with overseas researchers, the media and the public, and will
provide the "national voice" to policymakers and regulators
in the field of stem cell research. The secretariat is based within
the Research Councils in Swindon and operates under the guidance
of a Steering Committee of eight members chaired by Lord Naren
Patel of Dunkeld.
The UKNSCN has submitted the following written
evidence on behalf of the UK stem cell research community. However,
given the short time available to collate evidence, the Select
Committee is invited to note that the following evidence has essentially
been prepared through the Steering Committee and a handful of
selected academics from within the community. The opportunity
to consult more widely was significantly limited.
EXECUTIVE SUMMARY
This document focuses on the appropriateness
of the legislative proposals for regulating the creation of hybrid
and chimaera embryos (animal-human) set out in the Government's
recent White Paper (December 2006), and on the impact of these
proposals upon UK stem cell research. It presents a balanced view
of the benefits, risks and requirements for the generation of
hybrid and/or chimaera embryos (animal-human) for research purposes
on behalf of selected experts in the UK academic research community.
The regulatory body governing the use of the embryos in research
is currently the Human Fertilisation and Embryology Authority
(HFEA). The Select Committee is invited to note the UKNSCN's view
that the current regulatory framework for embryo research via
the HFEA would not cover animal-human hybrid embryos since these
would be generated outside the IVF system and would have no fertility
application at all. New legislation and possibly an entirely new
regulatory body might be required, although the UK's current strict
Home Office guidelines for animal experiments may cover this work.
If that is indeed the case, then careful use of the current regulatory
framework for both human and animal embryo experimentation may
mean that there is no need for any further legislation. The UKNSCN
considers that any form of "blanket" ban on the generation
of animal-human chimaeras would be undesirable and that any new
regulation should foster scientific progress whilst preventing
misuse. At the same time, the UKNSCN recognises that the successful
development and implementation of such regulation is dependent
upon society's active consent in this new area of science.
1. Terminology
1.1 The UKNSCN considers that the use of
the term "chimaera" for animal-human embryos generated
using current somatic cell nuclear transfer (SCNT) technology
is both misleading and unhelpful. It is misleading because it
implies the mixing of chromosomal DNA from animals and humans
(not the case with SCNT) and it is unhelpful because it refers
to the beast of classical Greek mythology which manifests the
head of a lion, the body of a goat and the tail of a serpent—quite
literally a monster created by the grafting of tissues from different
organisms, rather than anything generated by genetic recombination.
Developmental biologists have used the term "chimaera"
for any organism or embryo that contains the genomes from two
different individuals, either from the same or different species,
which never become mixed in the same cell. By this definition,
animal-human embryos generated by SCNT are not chimaeras, save
that they contain a small amount of animal mitochondrial DNA as
well as human nuclear DNA. This issue is discussed further in
paragraph 1.3 below.
1.2 The Select Committee might therefore
wish to consider adopting the terminology "animal-human hybrid
embryos" to refer to the embryos which some researchers are
seeking HFEA permission to generate using SCNT technology. Even
this term is not wholly scientifically accurate and may, of course,
not be palatable to the general public either. A more correct
term would be "cybrid" (literally, cytoplasm hybrid),
indicating that the embryo is essentially human and contains a
vanishingly small amount of animal genetic material. A further
new alternative term might be "composite". Scientifically
accurate terminology is vital in deciding what might be prohibited
and what might be permissible under regulation in any new legislation.
1.3 The nature of mitochondrial DNA/nuclear
DNA chimaerism has generally not been very well explained in the
media. The number 99.5% has been suggested for the percentage
of human genetic material, though the reality of the situation
is that we do not know the precise division. If one divides the
absolute amount of human DNA by the absolute amount of mitochondrial
DNA then one reaches something approaching this figure. However,
if one divides the unique genetic content of a mitochondrion into
the total haploid human genome then the figure is closer to 99.9995%.
2. Utility of Hybrid and/or Chimaera Embryos
for Research
2.1 The advantage of using animal-human
hybrid embryos lies not in their hybrid nature per se but
purely in the fact that the use of an animal oocyte overcomes
the problem of the shortage of human oocytes and the associated
ethical issues. This means that it will be feasible to investigate
far more thoroughly how it might eventually be possible regularly
to create SCNT embryos for therapeutic cloning. Success rates
for generating embryos by SCNT are low in all vertebrates, due
to key genes being switched off in somatic cell nuclei, and there
is a need to better understand this process. In addition, animal
oocytes are generally available fresh, unlike human oocytes which
are predominantly frozen. Research experience thus far has shown
that the success rates for SCNT are improved through the use of
fresh oocytes as opposed to frozen oocytes. Furthermore, and perhaps
most importantly, the use of the approach to speed the development
of effective protocols for the generation of cloned embryos (and
hence embryonic stem cells) from specific individuals with a genetically-based
disease will enable detailed research into the nature of the disease
and possible therapeutic strategies. It is too soon to say whether
hybrid patient-specific ES cells would have a direct role in therapy,
partly because of the ethical considerations, which would have
to be fully and openly debated, but also because of the potential
"conflict" between mitochondrial and nuclear gene products
derived from different species. No-one is proposing the use of
ES cells from hybrid embryos in stem cell therapy and prohibition
of such activity is already implicit in the EU Tissue Directive;
stem cell lines will be generated for research purposes only in
order to demonstrate the principles of the approach.
2.2 The availability (under current regulation)
of fully human embryos for research purposes in the UK means that
the generation of animal-human hybrid embryos is not strictly
necessary and has no real utility per se. If more human
oocyte donors were encouraged to come forward and consent to their
use for research purposes, then the requirement for animal-human
hybrid embryos would evaporate and the HFEA would retain full
regulatory control of the embryo research field.
2.3 The Select Committee is invited to note
that the scientific evidence for being able to successfully produce
animal-human hybrid embryos is in relatively short supply. There
is one key research paper from Professor Huizhen Sheng's team
in Shanghai, China published in 2003 which reports the derivation
of stem cell lines from enucleated rabbit eggs reprogrammed by
the transfer of human nuclei from skin cells. To the best of UKNSCN's
knowledge, this research has not yet been adequately reproduced
and further proof-of-concept research is necessary.
2.4 The utility of studies with animal-human
chimaeras, as distinct from animal-human hybrid embryos, lies
in their facilitation of our basic understanding of human ES cells
and our need to definitively assess the function of differentiated
cells arising from them. This knowledge is pivotal in our ability
to safely translate human stem cell research into clinical applications
in regenerative medicine. Such experimental chimaeras would be
required to exist for approximately three days in vitro
and would therefore not reach the stage where they become protected
by the Animal Scientific Research Regulations.
3. Ethical Benefits in the Generation and
Use of Hybrid and/or Chimaera Embryos
3.1 The UKNSCN considers that the positive
ethical benefit in generating animal-human hybrid embryos derives
from not having to use consented oocytes from human donors. Not
only are these in short supply, but they can only be obtained
by hormone treatment to induce superovulation. As with any medical
intervention, this carries a degree of risk, in this case the
risk of ovarian hyperstimulation syndrome.
4. Necessity and Alternatives
4.1 The UKNSCN believes that hybrid animal-human
embryos are probably necessary in the short-term if clones (and
subsequently ES cells for research) are to be made on a regular
basis in sufficiently large numbers for experimental purposes.
4.2 There are two possible alternatives,
only one of which is a proven to work thus far. The first is through
the use of donated human oocytes. The second alternative would
be the ability to reprogram any tissue (adult) cell so that it
becomes or behaves like a pluripotent embryonic stem cell. Recent
ground-breaking research from Japan has reported that this might
be possible simply by expressing four specific transcription factors
in a fibroblast. This is essentially "proof-of-principle",
but it will be quite some time before this is likely to be useful
(not least because it entails introducing strong expression vectors
into the cells). The work needs to be replicated and performed
routinely first, in line with accepted due scientific process.
Nonetheless, if the potential becomes a reality, then there will
no longer be any need to use donated embryos, or produce them
through somatic cell nuclear transfer, in order to generate human
embryonic stem cells for research purposes. Until this research
produces a reliable technology however, it may be argued that
the creation of human-animal hybrid embryos for generating stem
cells should be permissible (under current regulation) in the
short-term.
5. Ethical Objections to the Generation of
Hybrid and/or Chimaera Embryos for Stem Cell Research
5.1 The UKNSCN believes that the ethical
objection to the generation of hybrid and/or chimaera embryos
for stem cell research centres quite simply on the view that human
and animal genetic material should not be mixed, whether one is
talking about chromosomal DNA or mitochondrial DNA. For many,
the mixing of genetic material from human and animal species is
a taboo, though genetic "mixing" is already a widespread
practice in both academic research and commerce. For example,
many human protein drugs (eg erythropoetin) can only be manufactured
by inserting a relevant human gene (or genes) into an animal cell
in order to obtain the correct glycosylation of the final patient
therapy. The fact that the animal genetic material (mitochondrial
DNA) carried over during the SCNT process is almost certainly
in no way part of what defines that animal as being distinct from
a human will probably not carry much weight with the general public.
Clearly, however, some forms of mixing of human and animal tissues
have become generally acceptable in that animal organs and tissue
derivatives (such as heart valves) are used in transplantation.
6. Scientific and Public Opinion
6.1 The UKNSCN believes that the scientific
community in the UK is largely in favour of the generation of
hybrid animal-human embryos for stem cell research, though there
are several detractors from this view. However, the detractors
do not generally object on ethical grounds but rather on the basis
that the generation of hybrid animal-human embryos is probably
unnecessary in the UK when researchers already enjoy a permissive
(but tightly regulated) research environment which allows the
use of 100% human embryos. They generally wish to see more human
donors consenting to the use of oocytes for research purposes.
6.2 There is a genuine concern amongst some
scientists that the UK public has thus far trusted science with
the derivation of human ES cell lines and even therapeutic cloning,
but with very little so far to show by way of patient therapies.
The latter will take time but, against this background, the UKNSCN
is aware of the view that it is not yet time to move to the next
level (namely animal-human hybrids) which would appear to have
much less public support at present.
6.3 The UKNSCN believes that public opinion
has not been assessed sufficiently, despite the on-line public
consultation conducted by the Department of Health in 2005. Certainly,
the small number of responses received during this consultation,
that were the basis for the comments in the White Paper, can in
no way be viewed as a representative cross-section of the UK population.
It is the view of several stem cell researchers in the UK that
once the nature of the research and its aims are explained properly,
and that the public recognises the media's tendency to stir up
what might be colloquially referred to as the "yuk"
factor, then a large proportion of the general public will be
supportive. Indeed, an ethical scales argument may work well in
helping to crystallise opinion—does the public prefer to
see lots more women donating oocytes for research (in a procedure
that is not without risk) or to see fresh oocytes utilised from
cows that have already been slaughtered for the meat industry?
January 2007
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