The use of human stem cells for cell therapy is under debate
in Denmark. According to the Act on Medically Assisted Procreation
from 1997 Danish law has permitted the utilisation of human embryos
exclusively for research purposes to improve infertility treatment
by in vitro fertilisation or pre-implantation diagnostics.
However, on May 27 this year Parliament approved an amendment to
this Law permitting the use of in vitro fertilised eggs in
excess from infertility treatment for research with the purpose
of achieving new knowledge leading to the improvement of the possibilities
of treatment of diseases in humans. Out of the total of 179 seats
94 were in favour while 8 voted against.
Today, patients having lost the ability to regenerate blood cells
can be treated by transplantation of bone marrow which contains
adult stem cells that can differentiate into any type of blood cell.
In the future stem cell therapy may be used to treat other serious
diseases including Parkinsons, Huntingtons chorea, diabetes type
I, heart muscle malfunctioning and liver damage, for which current
therapies are inadequate. The hope is to be able to cure diseases
by implanting stem cells for replacement of sick or dead cells and
tissue. However the research is at an early stage and more detailed
scientific knowledge is needed to establish a systematic basis for
evaluation of the potential of different types of stem cells and
the utilisation of stem cell therapy. This can not be achieved by
only studying stem cells from adults, but also requires investigation
of stem cells from human embryo and foetal tissues. The extent to
which it is acceptable to use stem cells from these sources has
been one of the key ethical issues of the debate.
The biological background
Stem cells are cells that can develop into mature, specialised
cells in order to generate and regenerate tissue and organs securing
the functions of the human body. A stem cell can divide into identical
copies, a process which in principle can go on indefinitely. The
properties of stem cells depend on their developmental stage and
the source from which they are isolated. The characteristics of
embryonic, foetal and adult stem cells are briefly summarised:
Embryonic stem cells exist in the 4-6 days old early embryon
which is called the blastocyst. At this stage individual cells can
no longer develop into a full grown human being, but they have the
potential of differentiating into any type of cell or tissue. These
cells are denoted pluripotent. Embryonic stem cells can be obtained
from excess fertilised eggs from infertility treatment.
Embryonic cells can divide and give rise to new cells and thereby
form cell lines. In principle, endless numbers of embryonic stem
cells can be derived from one cell line. These cells can be preserved
frozen and cultured after thawing.
Foetal stem cells (5- 8 weeks old) can be derived from cells
of the gonads of the foetus. Their differentiation potential is
expected to be identical to the embryonic stem cells (pluripotent)
but the duration of self multiplication is considered to be shorter
than that of the embryonic stem cells. Foetal stem cells can by
obtained from spontaneously aborted foetuses.
Adult stem cells are isolated from umbilical cord blood
and a number of tissues including bone marrow. Their differentiation
potential seems significantly limited compared to embryonic stem
cells. Some adult stem cells are multipotent meaning that they can
give rise to several cell types in an organ. The so called progenitor
cells are more differentiated and give rise to only one cell type
as known from renewal of skin. Adult stem cells are responsible
for cell renewal and tissue repair from the early postnatal stage
and for the rest of the life. Adult stem cells and progenitor cells
are encountered in low numbers and are not easily isolated. Enhancing
their numbers in cell cultures has proven difficult in many cases.
International ongoing research programmes with transplantation
of adult stem cells and progenitor cells have encountered problems
with immunological rejection of the transplanted cells. If this
obstacle is not overcome, treatment would require immunosuppressive
medication for the rest of the patients life. The best way of avoiding
rejection after cell transplantation remains to be solved.
Stem cell therapy involving cell nuclear replacement
One strategy proposed to solve the problem of immunological rejection
is to replace the cell nucleus of an unfertilised egg (oocyte) with
the nucleus of a healthy, somatic cell obtained from the particular
patient. The advantage of this procedure is that the merged cell
is 98-99% genetically identical with the donor. From the merged
cell a blastocyst can be formed from which embryonic stem cells
can be isolated. Cell nuclear replacement (CNR) is the key to reprogramming
of the adult cells nucleus. The oocyte genetically reprogrammes
the transferred nucleus enabling it to direct the development and
growth of a whole new organism. However by isolating the embryonic
stem cells from the blastocyst, the growth process is terminated
and no new organism is developed. This technique can be used to
form pluripotent embryonic stem cell clones from which stem cells
for treatment of diseases can be derived. Therefore it is denoted
therapeutic cloning.
CNR was used to create the sheep, Dolly, and other mammalian species.
The organism formed this way is almost completely identical to the
individual from which the cell nucleus was taken and the technique
is therefore called reproductive cloning. In Europe the submission
of human cells to reproductive cloning is not accepted under any
circumstances, being it fundamental, biological research or infertility
treatment.
Stem cell research in Denmark
In Denmark a significant part of the stem cell research is undertaken
and coordinated by The Danish Centre for Stem Cell Research which
was established in 2002 based on 9 existing research groups from
universities and private research institutes including The University
of Southern Denmark, Odense and Hagedorn Research Institute. At
the same time a Stem Cell Research School for PhD-students was established
with the participation of additional 7 research groups. A number
of research projects are using human adult stem cells from umbilical
cord blood and bone marrow. In other projects embryonic stem cells
from mice are used. The Hagedorn Research Institute which is a part
of Novo Nordisk A/S is performing stem cell research focused on
the development of a therapy for diabetes type I.
Recommendations to Parliament
In January 2001 The Danish Parliament initiated an investigation
of the potentials and risks of human stem cells research and stem
cell therapy. The report on the investigation was finalised in October
2002. Regarding research using human stem cells the investigation
recommended that
- a public debate is initiated,
- a political resolution regarding utilization of embryonic stem
cells in research is established,
- if – as a result the resolution process - it is found necessary,
the preparation of legislative work is commenced.
The recommendations to Parliament were summarised in seven key
points mainly addressing issues related to research using embryonic
stem cells and the need for permits and regulations specifically
regarding:
- use of excess fertilised eggs from infertility treatment
- in vitro fertilisation of eggs but not as part of infertility
treatment
- formation of embryos via nucleus transfer from somatic cells
- use of embryonic stem cell lines
- information and consent from couples and/or women wishing to
donate eggs
- imported embryonic stem cell lines
- utilisation of adult stem cells
It was made clear that allowing the use of embryos for stem cell
research would require an amendment to the existing Act on Medically
Assisted Procreation. Taking the step further to allow formation
of embryos with the sole purpose of stem cell research would in
addition require an amendment to Denmark’s ratification of the Convention
on Human Rights and Biomedicine of the European Council.
Public hearing
The Minister of Science, Technology and Innovation invited for
a public hearing on the subject in January this year. The presentations
of 17 experts representing science, industry, social economics,
justice, ethics and philosophy were debated with 25 politicians
and 150 participants representing societies, associations, experts
and private persons.
Ethical dilemma
Can the perspectives of developing new medical treatments justify
the ethical dilemmas regarding utilisation of embryonic stem cells
?
According to Danish law, human life starts at the time of fertilisation.
In the debate it was further emphasised that any embryo is unique
and irreplaceable and should therefore not be treated as a subject
for investigation. As a consequence research in embryonic stem cells
is incompatible with due respect to human life and ethical considerations
to the embryo. However research in adult stem cells does not imply
an offence against the respect of human life.
In a different point of view based on a similar discussion of the
ethics related to provoked abortion, a distinction is made between
the new born baby and the fertilised egg: A new born baby is a human
person whereas a fertilised egg is not. How can the ethical and
legal status of the new born baby and the fertilised egg then be
the same ? From this point of view the value of human life gradually
changes from strict biological creation of the embryo to creation
of the human character of a person. A ban on the utilisation of
embryos can therefore be regarded as a governmental enforcement
of a particular interpretation of the value of the beginning of
human life. The perspective of developing a treatment for serious
diseases can in some instances be viewed as more valuable than the
value of the fertilised egg and the very beginning of human life.
Economic aspects
Presently the investments in the development of new and better
therapies for health care are increasing dramatically. However,
the problem for many seriously sick people is not the lack of new
treatment methods but rather that the public health care system
does not have sufficient funds and resources to implement and carry
out these treatments. Therefore an estimate of the costs of stem
cell research to develop a suitable therapy was requested.
However, as stem cell research is at an early stage it is difficult
to estimate the costs of research and development. In relation to
the cost benefit discussion it was argued that if stem cell therapy
could successfully be used to cure a disease such as diabetes type
I, resources for the treatment of late complications and disabilities
related to the disease would be saved.
Requests of the scientists
In relation to treatment of diabetes type I it was clearly stated
that the only stem cells presently known to be able to differentiate
into insulin producing beta cells are embryonic stem cells. The
quality and the progress of the research depends on having access
to well defined stem cells and stem cell lines which can be achieved
by using embryonic stem cells. Furthermore there will be a need
to create different stem cell lines for different types of tissue.
The limitations of research only using adult stem cells were emphasised
and the scientists concluded that there is a need to be able to
undertake research using embryonic stem cells under proper legally
regulated and controlled conditions.
The permission
International stem cell research is moving rapidly and the use
of cells from human embryos has already been permitted in a number
of European countries including Sweden and the UK. It has been possible
for Danish scientists to import embryonic stem cell lines from these
countries.
With the amendment to the existing Danish law it is now possible
for Danish scientists to investigate embryonic stem cells from national
sources from September 1, 2003 . Only stem cells derived from up
to 14 days old human embryos developed from in vitro fertilised
eggs formed in excess for infertility treatment can be used. These
are the same rules applied in Sweden and Finland, which do not the
permit formation of in vitro fertilised eggs for research
only and therefore are not interfering with the Convention on Human
Rights and Biomedicine of the European Council. In Denmark embryonic
stem cell research must be approved according to the rules of the
scientific ethical committee system.
Fast development within the area will probably require continued
surveillance and perhaps frequent adjustments of the regulations.
The Minister of Internal Affairs and Health added in his comments
to the amendment that the legislation on this area will be subject
to a general discussion at the next session starting October 2003.
With the present regulations it is not permitted to form stem cells
by cell nuclear replacement (CNR) because this involves the formation
of a fertilised egg for research purposes only. The strategy proposed
to solve the problem of immunological rejection of stem cells by
CNR and therapeutic cloning is so far pure speculation and is not
the direction in which leading Danish scientists foresee the research
to develop.
With the permission to use stem cells derived from in vitro
fertilisation treatment Danish scientists can now undertake research
using embryonic stem cells under proper legally regulated and controlled
conditions. This will have a significant impact on the development
of Danish stem cell research and the related biomedical industry.
But even with an intensive research effort it estimated that a given
therapy will take 10 –20 years to develop.
References
Amendment to the Act on Medically Assisted Procreation, proposal
no L209, May 2003 (in Danish)
Forslag til lov om ændring af lov om kunstig befrugtning i forbindelse
med lægelig behandling, diagnostik og forskning m.v.(Forskning på
embryonale stamceller). (www.folketinget.dk)
Banda, Enric (2002) Human stem cell research: scientific uncertainties
and ethical dilemmas. European Science Foundation Policy Briefing
18: 1-8. European Science Foundation, Strasbourg, France (www.esf.org).
BIOSAM (2003) Embryonale stamceller, Høring om anvendelse af stamceller
i forskning og behandling. (Embryonic Stem Cells, Hearing about
utilization of stem cells for research and medical treatment) Teknologirådets
rapporter 2003/1, Teknologirådet, Copenhagen , Denmark (tekno@tekno.dk)
pp 186
Danish Biotechnology Conference IX, (May 2003) Eucaroyte Engineering,
Proceedings. Danish Biotechnology Forum, c/o Department of Life
Sciences, Aalborg University, Denmark (www.biotechforum.dk)
Genteknologiudvalget (2002). Fremtidens bioteknologier – muligheder
og risici (Future biotechnologies – potentials and risks). English
summary . The Danish Ministry of Science, Technology and Innovation,
Copenhagen, Denmark (www.vtu.dk). pp 188
The present article is also to be published in BioCommerce
Data’s Biotechnology Company Compendium 2003/4: Europe and is reprinted
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