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.
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.
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.
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.
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
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:
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.
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.
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.
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.
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.
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.
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)
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The present article is also to be published in BioCommerce Data's Biotechnology Company Compendium 2003/4: Europe and is reprinted in BioZoom with permission of BioCommerce Data Ltd, UK.