Jill Trewhella
Deputy Vice-Chancellor (Research)
18th March 2011
The Honourable David Heerey QC
Legislative Review Committee
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
By email to Sarah.Busby@nhmrc.gov.au
Dear Mr Heerey,
Re: Public Submission to the Prohibition of Human Cloning for Reproduction and
Research Involving Human Embryos Act 2006 (Amending Acts) Review Committee
We believe that this review is justified and timely given the significant advances seen in
stem cell research since the establishment of the legislation in 2006 and the significant
positive impacts that these developments could potentially have on the health and well
being of people worldwide. We support the review and appreciate the opportunity to
make a submission.
Executive Summary
Our key recommendations are as follows:
1. We propose that the existing legislation should remain in place to allow research
involving human embryos and stem cell lines created by somatic cell nuclear
transfer to continue. Our proposal is supported by the results of community
surveys which indicate that levels of community support for this type of research
are similar or higher than they were in 2006.
2. The wording of the current legislation prohibits the insertion of three genomes
(either mitochondrial or nuclear) into an embryo. We believe that the legislation
was developed because of concerns about the insertion of three nuclear
genomes into an embryo. We propose that consideration is given to amending
the legislation to allow for the insertion of mitochondrial genomes into an embryo
to allow research into diseases caused by mutations of mitochondrial DNA to
proceed.
3. We note the potential benefits of allowing the creation of admixed blastocysts
(cybrids) for research purposes and that Singapore and the United Kingdom are
now allowing this practice. We note also that there is limited support for this
practice in Australia and that any attempt to amend the legislation to permit the
creation of admixed blastocysts is likely to require a protracted period of public
Room 646, Jane Foss Russell Building
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education and consultation. We therefore recommend that the prohibition
against the creation of admixed blastocycsts should remain.
4. Current legislation does not allow the creation of human embryos for research
purposes. We propose that this legislation is upheld, but that efforts are
undertaken to educate and inform the public in this area in anticipation of a future
shift in community perspective.
5. Current legislation does not allow for the payment of oocyte donors other than
the reimbursement of direct expenses. We propose that this legislation is upheld,
but that efforts are undertaken to educate and inform the public in this area in
anticipation of a future shift in community perspective.
6. To reduce the administrative burden on researchers in this field, we propose that
consideration is given to clarifying and simplifying the review and approval
process for research that involves human embryo stem cell lines that have been
prepared using protocols approved by recognized licensing boards and HRECs.
These recommendations are detailed in the attachment. Please contact me if you would
like to discuss any aspect of this submission.
Yours sincerely,
(Signature removed for electronic distribution)
Professor Jill Trewhella
Deputy Vice-Chancellor (Research)
Attachment
University of Sydney Submission
Re: Public Submission to the Prohibition of Human Cloning for Reproduction and
Research Involving Human Embryos Act 2006 (Amending Acts) Review Committee
Developments in embryonic stem cell research – including the actual or potential
applications of such research
It is important to note the significant developments in stem cell research since 2006.
Research involving the autologous or allogeneic transplantation of adult somatic stem
cells continues to advance and, while the best evidence continues to be for treatment of
malignant or immune disease, early studies suggest that autotransplantation of
haematopoietic or mesenchymal stem cells may have regenerative capacity in the
treatment of hepatic, pulmonary, cardiac, neurological and arthritic disease.
Over this period human ESC research has also provided important insights into normal
and pathological cellular biology, reproduction and embryogenesis and the creation of
disease models and systems for predictive toxicology and drug screening. 1 Human
embryos have now been created by SCNT and it is only a matter of time before human
ESC lines are derived from SCNT embryos. Animal studies of embryonic stem cells have
also shown promising results in the treatment of spinal injury, neurodegenerative and
demyelinating disorders and retinal disease and the first Phase 1 clinical studies involving
adults with spinal injury and stroke and children with macular dystrophy have begun.2,3,4
Coincident with this, a series of other developments in related fields of stem cell research
have also created enormous interest, most notably the derivation of induced pluripotent
stem cells (iPS cells) from non-gonadal tissue by the forced expression of specific genes
in adult somatic cells by researchers in Japan and the United States. 5 iPS cells, which
resemble embryonic stem cells in terms of their morphology, mitotic activity, telomerase
activity and expression of stem cell genes and proteins, have undoubtedly been an
important advance as they allow generation of stem cells without the use of IVF or SCNT
human embryos, do not require the use of donor oocytes, and avoid the problems of
immune rejection or graft versus host disease because they may be autologously
generated.6 But while proof-of-concept and animal studies of iPS in a range of
degenerative disorders show great promise, recent research suggests that iPS cells may
have a slightly different gene expression profile to human embryonic stem cells, have
limited differentiation capacity and undergo premature aging, and significant hurdles
remain to overcome with regard to the efficiency and safety of iPS cells before human
trials can begin.7,8,9
Recent research has also demonstrated that nuclei from 'terminally differentiated' adult
somatic cells can be induced (‘reprogrammed’) to express genes that are typical of
embryonic stem cells or of other lineages, and differentiated to form other cell types,
thereby enabling autotransplantation of normal tissue to areas of disease, or the
generation of new organs or tissues using tissue engineering technologies. 10,11,12
But while developments in iPS research and in cellular reprogramming show promise,
neither their emergence nor the fact that human embryonic stem cell research has not
(yet) translated into medical therapies, provides a reason for prohibiting ESC research.
There are a number of reasons why this is so. First, it remains unclear whether human
embryonic stem cells, reprogrammed adult somatic stem cells or iPS cells will prove to be
bioequivalent or offer alternative or complementary cellular therapies. 7 Second, each of
these areas face significant clinical and technological challenges, such that the realisation
of clinical benefits from stem cell research may take decades. Third, the stem cells
derived from SCNT may also yield benefits other than medical therapies, including cell
lines for drug screening and for research into early embryonic development, normal
organogenesis and certain disease states. Fourth, the notion that advances in one field of
research should mean that researchers are prevented, by law, from exploring another
related field of research is antithetical to the principles and practices of science. Fifth,
Australia’s existing regulatory framework provides the most effective means for ensuring
that research is important, rigorous and ethically sound in its design and conduct. And
finally, the moral, social, clinical and scientific environment in which research is done will,
itself, influence the trajectory upon which stem cell research travels. Should research
yield important benefits consistent with the needs and goals of the community – it will
prosper. Should it prove redundant or useless or totally at odds with the values of the
community – it will not.
For all of these reasons, and because human embryo and stem cell research enjoy high
levels of public support, it is our view that the existing legislation should remain in place
and we should not seek – again – to prohibit research involving human embryos or the
derivation of stem cell lines by SCNT.
Community standards
As was noted in Lockhart Review, Australia is made up of many different communities,
each of which have their own values, interests and beliefs, and any one person may
belong to many different communities at the same time.13 The idea that there is a single
‘community standard’ in relation to stem cell science or embryo research, therefore, is
deeply problematic.
Community surveys, however, provide a guide to public attitudes to hESC research and
recent surveys by the Dept Innovation, Industry, Science and Research suggest that the
majority of the community continue to support the use of hESC for medical research, with
70% of respondents indicating support (compared to 63% in 2005). There is no evidence,
therefore to suggest that community standards have changed sufficient to justify
substantive amendments to the existing legislation.
Given the importance of public trust in, and support for, these fields of research, it is our
view that ongoing public engagement and education regarding research involving
reproductive tissues and embryos and stem cell research should be supported.
Research or clinical practice which has been prevented as a result of legislative
restrictions
The existing legislation allows the creation of SCNT embryos and the use of ‘excess’ IVF
embryos for research purposes. The use of SCNT for reproductive purposes, the creation
of cytoplasmic hybrid or admixed embryos, the creation of embryos containing genomic
material from three individuals and the payment for gametes and embryos are all
prohibited.
Mitochondrial diseases:
The legislation currently prohibits any experiment that involves placing “three genomes”
into an embryo. This restriction was put in place primarily because it felt that to be
ethically problematic to manipulate human genomes by introducing genetic material from
a third ‘parent’. This restriction has been interpreted as preventing research into diseases
caused by mutations in the mitochondrial DNA, which is maternally inherited. This is
unfortunate, as the introduction of mitochondrial DNA from a third source may enable
normal development and so provide the basis of effective therapy. 14,15,16
While this disease affects only limited numbers of people and there is limited research in
this area in Australia, it is our view that consideration should be given to amending the
legislation to make clear that research issue insertion of genetic material from three
persons is acceptable where these genomes are mitochondrial, rather than nuclear.
Current prohibitions restricting combinations of three nuclear genomes should remain.
Creation of admixed blastocysts/cybrids:
In recent years, some countries (Singapore and the United Kingdom) have enacted
legislation to allow the creation of admixed blastocysts for research purposes under strict
regulatory control. It is our view that allowing the creation of admixed blastocysts would
likely facilitate research (in reproduction and in stem cells), would reduce the demands
being made on women to donate oocytes and may go some way to addressing the
existing global shortage of human oocytes for research, that the arguments against
allowing the creation of cybrids are weak, and that existing legislative and regulatory
controls, including requirements for HREC review and prohibitions on maturation and
transfer, would be sufficient to control this practice. At the same time, however, there
appears to be limited support from within the lay or scientific/professional community for
change to the existing legislation to allow this practice and it is unclear how much the
community would support the creation of admixed blastocysts. It seems likely that an
extensive period of public consultation and education would be necessary for any change
to receive wide public support.
It is our view, therefore, that the current prohibition against the creation of admixed
blastocysts should remain.
Creation of IVF embryos for research:
Australian legislation currently restricts the use of IVF embryos for research to those that
are created in the course of infertility treatment and are deemed supernumerary to the
couple’s reproductive needs. Creation of ‘sperm-egg’ embryos for research purposes is
prohibited. The basis for this distinction is threefold: that there is a cultural, moral or
ontological difference between SCNT and sperm-egg embryos; that the decision to use
an embryo for research should remain independent of the decision to create it; and that to
not use ‘excess’ embryos for research would be wasteful and disrespectful.
There are, however, a number of problems with this distinction. First, the definition of
‘spare’ or ‘excess’ embryo is unclear and inevitably arbitrary and is influenced by a series
of factors including PGD testing, social context, desire for family balancing, perceived
viability – factors that seem to have a tenuous link to the moral status of the embryo.
Second, the notion that embryos created sexually for the purposes of reproduction to
embryos created asexually is difficult to sustain. At the same time, however, it is
undeniable that reproduction has enormous cultural meaning and while we (as a society)
may tolerate the destruction of existing embryos for research purposes and the donation
of excess IVF embryos to other couples, we may baulk at the sexual creation of embryos
entirely for the purposes of research.
In the absence of clear evidence from the IVF community or from potential women who
may become either oocyte or embryo donors it is our view that the existing legislative
distinction should remain but that further public consultation should be conducted to
inform debate surrounding this issue.
Fair compensation/payment for oocyte and embryo donors:
Australia currently allows payment for direct expenses for oocyte donors but prohibits
payments for ‘indirect expenses’ or ‘valuable considerations’. While many countries have
taken this approach, in recent years others have allowed payment for indirect expenses,
such as loss of wages (eg Singapore) while others (eg United Kingdom) have taken
oocyte donation into account by offering subsidies to assist with the costs of IVF
treatments. These practices have attracted considerable controversy and it remains
unclear as to the whether such practices have the support of the IVF community, women
and the community more generally, and whether the ethical issues involved can be
balanced in such a way as to recognise the contribution, needs and autonomy of donors
and prevent the possible harms that may flow from the creation of a ‘market’ in oocytes
and embryos.
Given the existing uncertainty, it is our view that the existing prohibition should remain but
that extensive consultation with relevant stakeholders be conducted in order to better
inform the development of policy and practices in this area.
Activities of the Licensing Committee and the processes of HREC Review
While there is broad support for the role of the NHMRC Licensing Committee and the
current provisions for rigorous HREC review of stem cell research and research involving
human embryos, there is some confusion regarding the regulatory status of ES cells that
have already been made and are growing in culture and concern that the current system
for ethics approval for research involving the use of existing ES cell lines is excessively
bureaucratic. We also suggest that application and reporting requirements for a licence
for research are onerous and may act to inhibit research in this area. It is our view that
efforts should be made to simplify these processes and to support researchers with their
applications.
It is our view that consideration should be given to clarifying and simplifying review and
approval of research involving human ES cell lines that have been previously prepared
using protocols approved by recognised licensing boards and HRECs.
References:
1. Barbaric I, Gokhale PJ, Andrews PW. High-content screening of small compounds on
human embryonic stem cells. Biochem Soc Trans. 2010; 38(4):1046-50.
2. Khan A. First clinical trial begins for stem cell therapy. Los Angeles Times. October 12,
2010.
3. Sample I. Stem cells injected into the brain of a stroke patient in world first. `Guardian.
www.guardian.co.uk/science/2010/nov/16/stem-cells-injected-brain-stroke. Accessed
17/11/2010. (Article amended on 30 November 2010 to clarify that the Glasgow trial was
not the first to test stem cells in stroke.)
4. Vogel G. Second trial using human embryonic stem cells gets go-ahead. Science
Insider 2010. http://news.sciencemag.org/scienceinsider/2010/11/second-trial-usinghuman-embryonic.html. Accessed 1/12/2010.
5.StadtfeldM, Hochedlinger K. Induced pluripotency: history, mechanisms and
applications. Genes Dev. 2010;24(20):2239-63.
6. E. Kiskinis & K. Eggan. Progress toward the clinical application of patient-specific
pluripotent stem cells. J Clin Invest 2010; 120: 51-59.
7. Yu J, Thomson JA. Pluripotent stem cell lines. Gene Dev 2008;22:1987-97.
8. Hanna JH, Saha K, Jaenisch R. Pluripotency and cellular reprogramming: facts,
hypotheses, unresolved issues. Cell 2010;143(4):508-25.
9. Csete M. Translational prospects for human induced pluripotent stem cells. Regen
Med. 2010;5(4):509-19.
10. Szabo E, Rampalli S, Risueno RM et al. Direct conversion of human fibroblasts to
multilineage blood progenitors. Nature. 2010: ePub.doi:10.1038/nature09591.
11. Kaneko S, Otsu M, Nakauchi H. Reprogramming adult hematopoietic cells. Curr Opin
Hematol 2010; 17(4):271-5.
12. Yamanaka S, Blau HM. Nuclear reprogramming to a pluripotent state by three
approaches. Nature. 2010;465(7299):704-12.
13. Legislation Review Committee. (2005). "Legislation Review of Australia’s Prohibition
of Human Cloning Act 2002 and Research Involving Human Embryos Act 2002."
Retrieved 7 July 2005, from http://www.lockhartreview.com.au/.
14. Tachibana M, et al. (2009) Mitochondrial gene replacement in primate offspring and
embryonic stem cells. Nature 461(7262):367-72.
15. Craven L, et al. (2010) Pronuclear transfer in human embryos to prevent
transmission of mitochondrial DNA disease. Nature 465(7294):82-5.
16. Bredenoord AL and Braude P (2010) Ethics of mitochondrial gene replacement: from
bench to bedside. British Medical Journal 341:c6021.
Glossary
autologous
Involving one individual as both donor and recipient <autologous bone
marrow transplants>
allogeneic
Involving, derived from, or being individuals of the same species that are
sufficiently unlike genetically to interact antigenically
somatic
Any of the cells of the body that compose the tissues, organs, and parts
of that individual other than the germ cells
autotransplantation
The transplantation of a tissue or an organ from one site onto another on
or in the body of the same individual.
Haematopoietic
Of, relating to, or involved in the formation of blood cells
mesenchymal
Of, resembling, or being loosely organized undifferentiated mesodermal
cells that give rise to such structures as connective tissues, blood,
lymphatics, bone, and cartilage.
ESC
Embryonic Stem Cells are pluripotent stem cells derived from the inner
cell mass of the blastocyst, an early-stage embryo.
SCNT
Somatic Cell Nuclear Transfer, a laboratory technique for creating a
clonal embryo, using an ovum with a donor nucleus (embryos derived
from the patients' own cells, a concept commonly referred to as
"therapeutic cloning")
iPS
induced Pluripotent stem cells are a type of pluripotent stem cell
artificially derived from a non-pluripotent cell, typically an adult somatic
cell, by inducing a "forced" expression of certain genes. (Pluripotent stem
cells can give rise to any fetal or adult cell type).
mitotic
A process that takes place in the nucleus of a dividing cell
oocyte
An egg before maturation : a female gametocyte
organogenesis
The process by which the ectoderm, endoderm, and mesoderm develop
into the internal organs of the organism. The origin and development of
bodily organs.
pluripotent
Pluripotent cells are able to differentiate into all derivatives of the three
primary germ layers: ectoderm, endoderm, and mesoderm
hESC
Human Embryonic Stem Cell
IVF
In vitro fertilization (IVF) is a process by which egg cells are fertilised by
sperm outside the body, in vitro.
cytoplasmic
The cytoplasm is a thick liquid residing between the cell membrane
holding organelles, except for the nucleus.
mitochondrial DNA
Or mtDNA is inherited from the mother (maternally inherited).
blastocysts
a structure formed in the early embryogenesis of mammals,
Cybrid (or admixed
blastocyst)
a hybrid cell which combines the nuclear genome from one source with
the mitochondrial genome from another source.