last update: November 2022
Contact: Aurélie Halsband

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What are stem cells?

The term “stem cells” covers a non-uniform group of cells which, at least, share the following two properties:

• Stem cells are precursor cells of highly differentiated cells.
• After the stem cells have divided, the daughter cells can be either stem cells again (capable of self-renewal) or can differentiate into specific tissue, e.g. cardiac, neuronal, skin or muscle cells.
• Given that stem cells have the ability of self-renewal, they can, in theory, multiply indefinitely.
• Stem cells can differentiate into specific tissue, e.g. cardiac, neuronal, skin or muscle cells.

Stem cells can be identified first in the process of early embryonic development. The zygote is a totipotent stem cell (fig. 1). It develops in the early embryonic stages and forms the basis for all human tissue that is developed at later stages through specialisation or “differentiation”. The further the specialisation process of the daughter cells of a stem cell advances, the more the spectrum of their differentiation potential into various types of tissue is restricted.

Stem cells also go on to exist throughout the human life span in various types of adult human tissue, playing an important role in tissue regeneration and repair. They maintain the functionality of tissues and organs by supplying differentiated cells to replace damaged or dead cells. In common language use, the term “adult stem cells” has prevailed for this type of cells.

The classification and identification of stem cells is not entirely consistent and, therefore, may easily lead to misunderstandings. Stem cells are classified and identified either according to their potentiality or, as is more common, according to their derivation. Based on current research, the former are

• EC cells (embryonic carcinoma cells) from embryonic tumour cells,
• EG cells (embryonic germ cells) from foetal precursor cells of gametes,
• ES cells (embryonic stem cells) from early embryonic stages (blastocysts),
• iPS cells (induced pluripotent stem cells) from a reprogramming process.

The derivation of embryonic stem cells from blastocysts, during which the early embryo is destroyed, is ethically highly controversial.

How are human embryonic stem cells derived from blastocysts?

Currently, the technique most often used for the derivation of embryonic stem cells is that of in vitro fertilisation (IVF). The application of this technique has become an established procedure in reproductive medicine as a way of inducing pregnancy in cases of unwanted childlessness. During the infertility treatment, test tube embryos are directly inserted into the woman's uterus by catheter where they can then develop into a child (fig. 2). Early embryos created in vitro can, however, also be used for the derivation of embryonic stem cell lines.

Five to six days after fertilisation the zygote has matured into a blastocyst. It consists of an outer cell layer - the trophoblast, which forms the basis the foetal part of the placenta - and of the inner cell mass which develops into the foetus.

In order to derive stem cells (fig. 3), the trophoblast is destroyed either by using antibodies or laser technology. This renders any further development of the embryo impossible. The inner cell mass, which is now accessible, is placed and cultivated in a special culture medium in a culture dish. These cell culturing conditions allow for continued growth of cells without their further differentiation. This is the basis from which embryonic stem cells can be developed.

There are also other procedures which allow the extraction of ES cells without compromising the integrity and the embryo’s ability to develop. However, due to their low efficiency and the remaining reservations of the lawmaker, these procedures have not been used widely so far.

There are various imaginable ways of in vitro creation of blastocysts to be used for the derivation of embryonic stem cells. Accordingly, embryonic stem cells are subdivided into the following groups:

• ES cells generated from blastocysts created by in vitro fertilisation (IVF) (fig. 4).
• ES cells generated from blastcysts created by somatic cell nuclear transfer (SCNT) (so-called research or therapeutic cloning) (fig. 5).
• ES cells stemming from blastocysts created through parthenogenesis.

Embryonic stem cell lines have hitherto been produced mostly from embryos left over from IVF trials. Furthermore, embryonic stem cell lines have been isolated from embryos produced through parthenogenesis. Stem cells from cloned and parthenogenetic embryos probably distinguish themselves from those obtained from IVF embryos mostly in their immunocompatibility. 

In case of transplantations involving tissue derived from IVF embryonic stem cells, severe rejection reactions are very likely, similar to those triggered by foreign tissue grafts. In case of transplantations involving tissue derived from SCNT embryonic stem cells, so-called therapeutic cloning (see Research Cloning), on the other hand, no or only minimal rejection reactions are anticipated provided the cell nucleus donor and tissue recipient would be genetically identical.

The SCNT cell nuclear transfer method could, in principle, also be used for “reproductive cloning”, as has been shown in experiments with some species of mammals, where embryos from cell nuclear transfer were implanted in the uterus. The first successful experiment of this type was the creation of Dolly, the cloned sheep. However, this method is linked to high malformation and mortality rates.

What are the goals of research involving human embryonic stem cells?

Basic research focuses on basic relations and is not necessarily bound to concrete goals concerning its application.

Basic research
Human embryonic stem cells are of great interest both for basic research and for clinical research. 

In the context of basic research, the main focus lies on gaining insight into the molecular mechanisms of individual cell specialisation as well as on examining the organisation of cells in situ. Furthermore, the goal is an improved understanding of the development and regulation of early stem cell stages as well as of the mechanisms behind the ability to proliferate and differentiate. In addition, some research successes have been subject of special attention in the past few years:

In the context of clinical research there are hopes that embryonic stem cells may be used to help in the creation of tissue substitutes, in particular in the case of tissues which have only limited or no natural capacity for renewal, such as neuronal tissue. The current debate concentrates on the use of embryonic stem cells in the treatment of diseases such as Parkinson's Disease and Type I Diabetes, as well as diseases of the cardiovascular system. A further goal of the aforementioned use consists in being able to test active ingredients of potential pharmaceutical drugs on tissues created as described above. It is also conceivable for embryonic stem cells to be genetically modified and then be used in gene therapy, for example, to restore a destroyed immune system.

Induced pluripotent stem cells
In 2007, two groups of researchers recently published independently of each other techniques to reprogram human somatic cells successfully so that they show essential characteristics of embryonic stem cells. Such cells are called induced pluripotent stem cells (iPS cells).

The techniques are connected with risks which have to be solved prior to therapeutic use. Various research groups are currently investigating to solve these. Previous techniques required the transportation of four genes (Oct4, Sox2, c-Myc and Klf4) into the respective cell for reprogramming. Viruses thereby served as a vehicle for transportation, as they infiltrate the DNA of the cell and modify it. Yet changes to the DNA can lead to genetic anomalies. These may affect single DNA elements or whole sections and can even alter the number of chromosomes. Depending on the technique being used, the mutations occur at different points of time and can even lead to a higher risk of cancer if they affect sections which control cell growth. A broad application of tissue cells obtained from reprogrammed cells for therapeutic use is therefore not feasible yet, despite clinical applications having already been conducted (more under “Clinical Research”).

Ethically, induced pluripotent stem cells provide the advantage of being gained by reprogramming adult cells instead of by destroying the embryo. With the help of known methods such as tetraploid embryonic complementation, however, it is theoretically possible to generate completely viable organisms, i.e. reproductive clones, from adult cells and iPS cells (more under III. Key Issues in the Ethical Discussion).

Stem cells cloning for research purposes
Leaving aside the ethical and legal problems, obtaining embryonic stem cells after cell nuclear transfer (so-called “cloning for research purposes” or “therapeutic cloning”) was technically not feasible for a long time. 

In May 2013, US-American research group from Oregon Health and Science University in Portland successfully obtained human embryonic stem cells from cloned embryos for the first time. The group of scientists led by Masahito Tachibana and Shoukhrat Mitalipov had in the first instance transferred the nucleus of adult human skin cells into enucleated donated oocytes, as it had already been described by the US-American group of scientists led by Andrew French in 2008. For the study of the scientists led by Tachibana and Mitalipov only a small number of oocytes was required, as the scientists were able to prevent an early death of the embryos by a systematically improved method. After a few cell divisions, the embryos were destroyed to obtain embryonic stem cells, what in other studies had not been possible or was not even attempted.

In April 2014 Robert Lanza from the biotechnology company ACT and Dong Ryul Lee from the Stem Cell Institute in Seoul issued the successful establishment of stem cell lines which they extracted from the skin cells of two adults, a 35-year-old man and a 75-year-old man, using a cloning method. It was thus possible to show, compared to the previous year, that stem cells can also be extracted using cell material which already display numerous genetic and biochemical alterations as well as suspected damages to the DNA. 

The aim of this therapeutic cloning is to produce a genetically identical replacement tissue from the somatic cells of the patients which does not get rejected. The stem cells obtained this way are similar to the ones obtained from fertilised embryos and can be differentiated to viable nerve cells, heart cells or liver cells. However, in november 2014 researchers of the University Medical Center Hamburg-Eppendorf published a study on the mouse model in the journal Cell Stem Cell, in which rejections to transplanted SNCT-ES cells had been recorded. The reason for such rejections are mitochondrial differences between the transplanted cells and those from the receiver. Mitochondria are cell components which serve the production of energy inside the cell. Given the comparatively low mitochondrial variability in mice, immune reactions could be possibly expected in humans. Researchers, though, still think SNCT is a promising path to new therapies if the immune reactions are circumvented.

The scientists emphasize that their research is aiming at therapeutic cloning, not at reproductive cloning. Whether this procedure of obtaining embryonic stem cells will ever be applied in medical practice is yet controversial due to ethical concerns regarding the creation and destruction of embryos, the physiological stress of the oocyte-donators and a potential expansion to reproductive cloning.

Research of ethically unobjectionable procedures
Basic research focuses on how human embryonic stem cells are cultivated, differentiated and manipulated. Some clues hint toward iPS cells being different to ES cells with regard to changes in the genome. Thus, the aforementioned processes can only be researched on ES cell lines. iPS cells or even adult stem cells provide no alternative for such research as of yet. For medical research ES cells are still regarded to be a golden standard against which alternatives are measured.

With regard to the production of replacement tissues, the method of transdifferentiation provides an ethically less objectionable alternative. By means of the transdifferentiation technique, attempts are made to use differentiated adult cells (such as skin cells) to generate other specialized cell types (such as nerve cells) without the detour via stem cells. Similar to the iPS technique, transcription and growth factors are used here in order to reprogram the cells. It is also possible to produce precursor cells of certain tissues.

No embryonic tissue is needed for transdifferentiation. Given that transdifferentiated cells are the patient’s own, they help avoid immune and adverse reactions, making them especially suitable for applications in regenerative medicine. The genetic modifications needed for their generation, however, bear the risk of malignant degeneration. The technology used to reprogram cells is currently being used to research genetic diseases.

Exclusively conducting research on animals is a further, occasionally discussed alternative to research on human embryonic stem cells. A usual argument for this is that the cultivation and mechanisms of differentiation of stem cells can be researched with stem cells from mice. Such research is additionally not regulated and pre-trials with mice often help plan and justify follow-up trials on human stem cells. Besides animal research being ethically controversial (see “Animal Experiments in Research”) there is a further problem concerning the applicability of their results to humans. The differentiation mechanisms of embryonic stem cells are partly controlled by different growth factors in mice than in humans.

Researchers working on further approaches are trying to circumvent possible ethical issues concerning the use of embryos in stem cell acquisition. For example, researchers are trying to cultivate stem cells that were isolated from amniotic fluid. It has been reported that human fat, muscle, bone, nerve and liver cells have been gained from such cells.

Translational Research
Translational research lies in the intersection of basic research and its application to concrete goals. This relationship bears particular significance when it comes to a relatively young research area like stem cell research.

An important goal is the clinical application of stem cells. Inter alia, translational research investigates how human embryonic stem cells differentiate, how they can facilitate a better understanding of the occurrence of certain diseases and how therapies can be developed using embryonic stem cells.

Finding answers to the following questions arising from basic research is the precondition for any application in regenerative medicine:

• How can embryonic stem cells be derived efficiently?
• Do all embryonic stem cell lines show the same properties?
• How can embryonic stem cells be genetically modified?
• How can the differentiation of daughter cells be regulated?
• What new methods and tools are needed in order to measure and control this differentiation in vivo and in vitro?

For both embryonic stem cells and adult stem cells, the following criteria must be considered with regard to their possible regular clinical applications:

• Proliferability: it must be possible to proliferate the stem cells in sufficient numbers.
• Differentiability: it must be possible to stimulate their differentiation into the required cell types.
• Purity: it must be possible to generate differentiated cells of one cell type only; i.e. pure cells instead of cell mixtures.
• Targeted integratability: it must be possible to transplant the cell or tissue replacement into the correct part of the body.
• Ruling out tumour formation: it must be guaranteed that there is no uncontrolled transplant growth or risk of tumour formation.
• Long-term therapeutic efficacy: the transplants must prove their functionality in the organism and their therapeutic effects on a long-term basis.
• Immune tolerance: the cell transplants should not be rejected by the immune system of the transplant recipient. 

Research on the differentiation of human embryonic stem cells
Since the gain of the first human ES cell lines in 1998, several advancements have been made in the field of research with embryonic stem cells. Through in vitro and in vivo differentiations of human embryonic stem cells it has been possible to generate both different progenitor cells and differentiated cells from human embryonic stem cells. Research in this area is taking place, in particular, on nerve cells, cardiac and vascular cells, blood cells, hepatic and pancreatic cells. The assignment of progenitor cells to certain tissue groups did not proceed through proof of their functionality but rather based on surface molecules created by the cells. In certain cases, progenitor cells gained from human ES cells were transplanted into model organisms, e.g. rats or even monkeys. Evidence of a functional participation of the cells in complex tissues could be provided.

In July 2006, the gain of sperm from murine embryonic stem cells was described. In 2009, the biotechnologist Kang Zou from Shanghai University published a study in Nature Cell Biology showing that injections of marked egg stem cells from adult mice into ovaries of sterile mice helped their procreation. In 2016, the team of Japanese stem cell researcher Katsuhiko Hayashi was able to produce egg cells from embryonic as well as induced pluripotent stem cells completely in vitro. After the artificial fertilization of the oocytes healthy offspring evolved. The technique, known as in vitro gametogenesis, could for example open up therapeutic possibilities against infertility. At the moment, the application of this technique to humans is not yet possible and, besides, ethically highly controversial.

Research on the development of diseases and new therapeutic options
Given the characteristics of differentiation of ES cells, these cells are especially suited for such research to thoroughly investigate a variety of developmental processes. For example, ES cells can be used to research the occurrence of specific diseases on a molecular level. Also, researchers hope to gain insights advancing the development of individually tailored treatments. Stem cell based models which help know specifics on efficacy and security more accurately than animal research are of interest for the development of new as well as existing drug treatments. In this context, so called organoids made from stem cells play an increasingly important role as model systems.

Researchers also hope that ES stem cells will help make the creation of tissue replacement possible, especially for tissue that shows little to no regeneration capability, such as nerve tissue. ES cells are suspected to be a sheerly inexhaustible source to replace cells and tissue due to their capability to multiply unboundedly. Such research aims at the application of ES cells to treatments for various illnesses, such as neurodegenerative diseases like Parkinson and multiple sclerosis, diabetes mellitus type 1, as well as cardiovascular diseases. Additionally, in light of the high prevalence of heart diseases in industrial states, the development of stem cell based regenerative treatments is being intensively researched.

In the area of tissue replacement, research on adult stem cells and iPS cells also plays a central role. Some therapeutic procedures in which adult stem cells are used, such as blood stem cell transplantation, are already widely used in clinics.

Clinical application of stem cell research
Central foci of clinical research are, i.a., the efficacy, compatibility and patient safety of medical interventions. An early clinical application has been regarded unrealistic for a long time. Stem cell-based therapies were only offered by dubious private clinics in countries without counteracting regulations. In the meantime, several clinical studies were carried out which give occasion to revise the previous assessment:

At the Atlanta-based Shepherd Center in the United States in October 2010, a patient with a spinal cord injury (multiple organ dysfunction) was treated with embryonic stem cells for the first time. The operation was part of a clinical trial by the biotech company Geron, and was approved by the US drug administration, the FDA, in January 2010. The aim of the phase 1 trial was firstly to examine the safety of the method when used in humans. Long-term, the trial aimed to help paraplegic patients regain sensation and mobility. As part of the GRNOPC1 trial, five patients were injected with around two million oligodendrocyte progenitor cells which had been previously derived from embryonic stem cells from a line generated in 1998. The researchers hoped that this method would allow oligodendrocytes to form that produce myelin - a substance which makes an essential contribution to conducting nerve impulses. The trial was discontinued in 2011 for financial reasons. 

In 2013, the biotech company Asterias took over the trial and the care of the test patients involved from Geron. Asterias has been continuing this clinical research since 2015 as part of the SCiStar study. The company is continuing to evaluate tolerability to the injection of AST-OPC1 cells derived from human embryonic stem cells. Varying amounts of progenitor cells are administered to patients who have suffered very recent spinal cord injuries. The interim results to date have shown a good level of tolerability and an improvement in motor function; however this is to be investigated further in follow-up efficacy studies. 

Further clinical studies were carried out from 2011 onwards on the therapeutic use of human embryonic stem cells in diseases of the retina. The patients taking part in the trial were either suffering from Stargardt disease (SMD or Stargardt macular dystrophy - a degeneration of the macula (part of the retina) which usually begins in childhood) or an age-related form of macular degeneration (AMD). Both forms impair the function of the retinal pigment epithelium in the retina of the eye and lead to blindness. A team of researchers led by Steven Schwartz at the University of California investigated the tolerability of an injection of retinal pigment epithelial cells developed from embryonic stem cells. To address ethical concerns about the use of embryonic stem cells, blastomere extraction was used on embryos from reproductive medical centres as part of the study. In this process, one of eight blastomeres or cells is removed from the embryo at a very early stage of development; as a result the embryo is generally preserved. 

During the course of the trial, patients suffering from SMD or AMD were injected with pigment epithelial cells derived from embryonic stem cells. These cells were to take over or support the function of the diseased cells. One eye per person was treated. In terms of tolerability and efficacy, the initial results were positive. A follow-up study carried out in 2014 by the same team on the medium-term to long-term tolerability and the procedure's treatment outcomes confirmed the results of the first trial. A long-term tolerability study followed.

The treatment of macular degeneration based on embryonic stem cells continues to be an active area of research. As well as proving the efficacy of such treatment, tolerability considerations are chiefly at the forefront of investigations, such as finding information on the frequency of tumour formations following injections of heterologous embryonic stem cells. These clinical trials are supported by research into the potential for a therapeutic use of induced pluripotent stem cells (iPS) with the same therapeutic goal.

Stem Cell Research Dossier

The following documents are a collection of relevant legal texts, guidelines and opinions on stem cell research from a number of European and non-European countries; the Stem Cell Research Dossier (to 2004); the University of Minnesota Medical School’s world stem cell map; and the Hinxton Group’s map of world stem cell policies.

1. International Regulations

There are no regulations directly relevant to research with human embryonic stem cells at either United Nations (UN / UNESCO) or at European level (Council of Europe / European Union). At both levels, however, there are opinions and regulations or regulatory efforts concerning the use of cloning methods in humans. Therefore, these documents are indirectly relevant to human embryonic stem cell research. Also of significance at European Union level are those regulations belonging to the European Union’s Ninth Framework Programme for Research and Innovation, Horizon Europe, which refer to joint funding of research with human embryonic stem cells.

UN / UNESCO
In its report ‘The Use of Embryonic Stem Cells in Therapeutic Research’ dated 6 April, 2001, UNESCO’s International Bioethics Committee (IBC) stated that the question of regulating research involving human embryonic stem cells was an ethical question and that it was not only the right but also the obligation of each individual society to discuss this question in its own right. Against this backdrop, the IBC encouraged governments to promote free and informed public debates in all countries at national level. The Committee recommended that in those countries where embryo research is allowed, it should be subject to state regulation in order to ensure adequate respect of the ethical principles. According to the Committee’s recommendation, the use of so-called ‘surplus’ embryos for stem cell research should be tied to the free and informed consent of the donors and research projects should be reviewed by ethics committees. Furthermore, the IBC advocated the careful assessment of the advantages and risks of alternative methods of stem cell derivation. The report reiterated that nuclear transfer should only be used in conjunction with therapeutic research.

In the ‘Report of the IBC on Updating Its Reflection on the Human Genome and Human Rights’ of 2 October, 2015, the IBC has come down in favour of a risk-averse legislation based on the precautionary principle at national and international level in view of new research findings such as induced pluripotent stem cells. According to the report, embryonic stem cell research should be “non-controversial” - i.e. it should satisfy as broad a cultural and ethical consensus as possible. The use of induced pluripotent stem cells instead of embryonic stem cells is a step in this direction. For the regulations governing cloning issues, see the In Focus section on Research Cloning.

European Union
The European Group on Ethics in Science and New Technologies (EGE), set up by the European Commission, states in its Opinion on the Ethical Aspects of Human Stem Cell Research and Use of 14 November 2000 that “in the context of European pluralism, it is up to each Member State to forbid or authorise embryo research. In the latter case, respect for human dignity requires regulation of embryo research and the provision of guarantees against risks of arbitrary experimentation and instrumentalisation of human embryos.” In the countries where it is permitted, it should be placed “under strict public control by a centralised authority - following, for instance, the pattern of the UK licensing body (the Human Fertilisation and Embryology Authority).” Moreover, the group deems “the creation of embryos with gametes donated for the purpose of stem cell procurement ethically unacceptable, when 'surplus' embryos represent a ready alternative source.” The group also declares “that, at present, the creation of embryos by somatic cell nuclear transfer for research on stem cell therapy would be premature since there is a wide field of research to be carried out with alternative sources of human stem cells (from 'surplus’ embryos, foetal tissues and adult stem cells).”

On 20 June, 2007, shortly after the Seventh Framework Programme (FP7) commenced, the EGE issued a further, more detailed statement on research projects and the use of human embryonic stem cells. Alongside the ethical criteria on research with human embryonic stem cells developed with regard to the Sixth Framework Programme for Research, a number of other criteria were cited. It pointed out that if alternatives to research with human embryonic stem cells were to be discovered due to scientific advances, the logical consequence would be to undertake both an ethical and bioscientific re-evaluation of research with human embryonic stem cells. It also referred to the rights of embryo donors and thus, in particular, the necessity of informed consent procedures regarding embryo donation.

Previous EU Framework Programmes are being continued and extended in the form of the large-scale EU funding programme Horizon Europe. The budget stands at around 95,5 billion EUR for the period from 2021 to 2027. The first of six clusters under the programme pillar "Global Challenges and European Industrial Competitiveness" is the research area "Health", for which a sub-budget of 8.2 billion euros has been provided to fund it. The focus here is on research into health determinants and disease processes as a basis for effective, evidence-based healthcare, the development of improved monitoring, prognosis and diagnosis methods, as well as the treatment of diseases and innovations for disease management. Focal points are among others research into health determinants and disease processes as a basis for effective, evidence-based health care, the development of improved monitoring, prognosis and diagnostic methods, the treatment of diseases and innovations in disease management. As part of these research goals, EU funding is planned for research work which limits itself to using previously established stem cell lines. The ethical framework for Horizon Europe is closely modelled on Horizon 2020 and the seventh Framework Programme (FP7 2007-2013). This ethical framework is based on the recommendations of the EGE on the occasion of the creation of FP7. In accordance with this, the preservation of ethically relevant boundaries is ensured by a three-tier system. Firstly, EU projects must be in harmony with the laws of the country in which they are carried out. In addition, all projects are to be examined using the peer review process in terms of the appropriateness and necessity of using human embryonic stem cells. EU funds may not be used for the derivation of new stem cell lines or for research work in which embryos are destroyed, for example to procure stem cells. Parliament and Council issued a joint regulation on 11 December, 2020 which set out the contents and conditions of the programme whereupon Horizon Europe entered into force on 1 January, 2021 and will run until 31 December, 2027.

Not least the issue of the potential patentability of stem cells is still to be clarified. The Federal Patent Court took the first step towards this for Germany in 2006. The issue of a European stem cell patent has been answered by the judgment of the Court of Justice of the European Union (CJEU) of 18 October 2011. This came in response to an application from the Federal Court of Justice (BGH) of 2009, which requested clarification in the case of Brüstle at European level. In its judgement, the court principally followed the opinion of the independent Advocate General of the Grand Chamber of the Court of Justice of the European Union, Yves Bot, and highlighted three points in particular: The court stated that “any human ovum after fertilisation, any non-fertilised human ovum into which the cell nucleus from a mature human cell has been transplanted, and any non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis constitute a ‘human embryo’”. The European Court of Justice also concluded: “The exclusion from patentability concerning the use of human embryos for industrial or commercial purposes set out in Article 6(2)(c) of Directive 98/44 also covers the use of human embryos for purposes of scientific research, only use for therapeutic or diagnostic purposes which is applied to the human embryo and is useful to it being patentable.” Furthermore, Article 6(2)(c) of Directive 98/44 excludes an invention from patentability “where the technical teaching which is the subject-matter of the patent application requires the prior destruction of human embryos or their use as base material, whatever the stage at which that takes place and even if the description of the technical teaching claimed does not refer to the use of human embryos.” Whether a stem cell obtained from a human embryo constitutes a human embryo or not is a question for which the Court gave no definitive answer; this question is “for the referring court to ascertain, in the light of scientific developments”.

In a further judgement by the CJEU on 18 December 2014, the judgement from 18 October, 2011 was amended. In the judgement, the CJEU made a decision on fundamental objections submitted on behalf of the UK Patents Court to a patent application of the Canadian biotech company International Stem Cell Corporation. With reference to the CJEU’s judgement in the Brüstle case of 2011, the UK government had requested clarification from the CJEU in this matter as relevant processes for the patent were based on the use of human embryonic stem cells, produced by parthenogenesis. However, the 2011 judgement expressly excludes this from patentability. In the judgement of 18 December, 2014, the CJEU however deviated explicitly from this point, following the recommendation of the Advocate General Cruz Villalón. According to the judgement, parthenotes, i.e. unfertilized ova that have entered a process similar to embryonic development due to chemical or electrical activation, are not human embryos, as they do not possess the inherent capacity of developing into a human being. The CJEU explained in its reason for the judgement that in principle it followed those of the judgement made in the Brüstle case but that recent scientific findings that had become available in the meantime had led to a re-evaluation of the classification of parthenotes as human embryos. 

On 13 September, 2013, the European citizens’ initiative (ECI) “One of Us” issued a statement on its website announcing that it had gathered the required number of signatures allowing it to voice its concerns directly to the European Commission, which would then be required to make a public response to the matter. Among other issues, the ECI was critical of the fact that research on embryonic stem cells and cloning processes was being partially funded with taxpayers’ money from EU member states although these countries prohibit research that presupposes the “use”, i.e. the destruction of an embryo. In the view of the initiators of the ECI, the judgement behind the landmark decision by the Court of Justice of the European Union of 18 October 2011 on the patentability of stem cell based biotech inventions would suggest that funding for research which involves the use of embryos should cease at European level. On 28 May, 2014, the European Commission issued a statement in which the legal situation hitherto was defended and the petition rejected. In the reasons given, it states that the regulations of the currently prevailing EU Framework Programme for Research and Innovation Horizon 2020 are formulated appropriately for this complex issue and satisfy the highest ethical standards. Furthermore, it indicated that in the Brüstle judgement of 18 October, 2011, which the initiators of “One of Us” referred to with regard to their aims, the CJEU itself had attributed its decision exclusively to its meaning in terms of patent law and stated that it was not intended to be applied to other areas of law, such as funding guidelines.

The International Society for Stem Cell Research (ISSCR)
The International Society for Stem Cell Research (ISSCR) was founded in 2002. It is an independent, non-profit organisation and aims to foster the exchange of information on stem cell research.

In December 2006, the ISSCR published a series of guidelines governing research with human embryonic stem cells. In accordance with these guidelines, researchers were to commit to upholding the guidelines and among other things should not clone humans for reproductive purposes, should only produce hybrids of humans and animals (chimeras) subject to strict conditions and should limit payment for egg cell donations. Furthermore, the ISSCR wanted to ensure that reputable scientific journals only published those studies which upheld these standards. 

On 12 May, 2016, the ISSCR published an update to its Guidelines for Stem Cell Research. The society was reacting on the one hand to new research findings, such as the generation of induced pluripotent stem cells, and on the other hand to the hype surroundings stem cells and the increased emergence of clinics offering scientifically doubtful stem cell treatments. As a result, the updated version demands improved communication between scientists and the public about the possibilities and limits of stem cell research.

2. Regulations in Individual Countries

For more details of the regulations governing stem cell research in individual European countries and around the world, please see the DRZE Expert Report Vol. 3 (currently available in German only) “Präimplantationsdiagnostik, Embryonenforschung, Klonen - Ein vergleichender Überblick zur Rechtslage in ausgewählten Ländern”.

Germany
The Embryo Protection Act, which came into force on 1 January, 1991, prohibits the production of an embryo “for any purpose other than the bringing about of a pregnancy.” Furthermore, it bans the use of an embryo “for a purpose not serving its preservation”. The Act makes it a punishable offence to cause “artificially a human embryo to develop with the same genetic information as another embryo, foetus or deceased person.” An embryo is defined in this context as “each totipotent cell removed from the embryo that is assumed to be able to develop into an individual under the appropriate conditions for that”. The Act thus bans the creation of embryos for research purposes. In the same way, the use of embryos for the production of stem cells, i.e. not for the purpose of their preservation, is also prohibited. The ban applies independently of whether these stem cells are totipotent or not and also extends to ‘surplus’ embryos. 

Whether the Embryo Protection Act also prohibits "therapeutic cloning" or whether there is a regulatory gap is subject of a controversial debate amongst legal experts.

The import and utilisation of embryonic stem cells, which are not totipotent, are regulated in the Stem Cell Act adopted on 28 June, 2002. According to this Act, the import and utilisation of these cells are only admissible subject to specific preconditions: they must have been “derived before 1 January 2002 in the country of origin in accordance with relevant national legislation there;” and the embryos from which they were derived must “have been produced by medically-assisted in vitro fertilization in order to induce pregnancy.” Moreover, they must “definitely no longer (be) used for this purpose.” Apart from these stipulations the Act also lays down that “no compensation or other benefit in money’s worth may have been granted or promised” for the donation of these embryos. Research activities involving stem cells must serve “eminent research aims” and must “have been clarified as far as possible through in vitro models using animal cells or through animal experiments.” Lastly, there must be scientific reasons to believe that “the scientific knowledge to be obtained from the research project concerned cannot be expected to be gained by using cells other than embryonic stem cells.” The question whether the preconditions are fulfilled must be considered “by a competent agency in its portfolio determined by ordinance by the Federal Ministry for Health.” This agency will be advised by an independent, multi-disciplinary Central Ethics Commission for Stem Cell Research.

The corresponding regulation of 18 July 2002 states that the competent authority is the Robert Koch Institute (RKI). A regularly updated overview of the research projects approved to date can be accessedd on the RKI website (April 2022: 177 projects approved).

The limited use made of the increased support available for stem cell research from EU funding is viewed as a special problem facing German researchers. Due to the restrictive legislation there have been only a few instances where German researchers are able to access EU support for stem cell research.

After long controversial discussions, the Parliament of the Federal Republic of Germany voted in favour of amending the German Stem Cell Act on 11 April, 2008. In the process, they agreed to postpone the cut-off date for importing embryonic stem cells from 1 January, 2002 to 1 May, 2007. The impetus for the renewed debate, and ultimately for amending the Act, came from position papers written by the German Research Foundation (DFG) and the German National Ethics Council in the years 2006 and 2007 respectively.

In addition, there is the issue of patenting research processes and research findings involving embryonic stem cells. In 1999, Bonn-based Professor Oliver Brüstle was granted the patent for deriving neural stem cells from human embryos. These neural cells were intended for treatment of Parkinson’s disease. The environmental organisation Greenpeace brought an action against this patent maintaining that it contravened public order and common decency as it involved the destruction of the embryos required. On 5 December, 2006 the Federal Patent Court declared the 1999 patent partially null and void with reference to the Embryo Protection Act and the Stem Cell Act. As the patented procedure necessarily involved the destruction of human embryos for industrial and commercial purposes, the Patent Court concluded that a patent application would be contrary to the principle of human dignity accorded to human embryos. Critics of this decision stress that patent protection is a necessary incentive for innovative scientific enterprises in this promising area of health care and reject the raised concerns about a commercialisation of stem cells with reference to the existing regulation of their derivation and cultivation.

In the course of the subsequent appeal proceedings, the German Federal Court (BGH) passed the case on to the Court of Justice of the European Union (CJEU) in the first instance in order to clarify several fundamental questions. The provisions of the landmark ruling of the CJEU from 18 October, 2011 were implemented into national law on 27 November, 2012. According to this ruling, the use of human stem cells obtained from embryos remains “not patentable” in Germany. However, the use of embryonic stem cells as such does not constitute a use of embryos, as stem cells do not possess the ability to initiate the process of development into a human being. Patents on the basis of embryonic stem cells are therefore entirely possible if the cell lines used for their production have been obtained without the destruction of an embryo. Hence procedures which include the use of cell lines obtained from embryos that are no longer viable are also patentable. Thus Brüstle, who had made an alternative claim which referred to these methods of obtaining embryonic stem cells, was initially granted the patent until it was revoked by the European Patent Office on 11 April, 2013 on the technicality that such methods of obtaining stem cells without harming or destroying the embryo were not yet public knowledge at the time when he applied for the patent. A further judgement by the CJEU on 18 December, 2014, specified which procedures and methods of stem cell derivation are legally permissible. Accordingly, procedures involving the derivation of human embryonic stem cells from so called parthenotes can constitute patentable inventions (see the section “European Union” above for more information on the patentability of human embryonic stem cells).

France
Embryonic stem cell research in France is regulated by the Public Health Code (Code de la santé publique) since 1994. The regulations stated therein were amended several times by bioethics laws (Lois relatives à la bioéthique). 

Since then, the production of embryos for research or commercial purposes as well as cloning for research and reproductive purposes have been prohibited in France. With Law 2011-814 of 7 July 2011 on bioethics, the legislation changed to the effect that research on embryos and embryonic stem cells is permitted under strict conditions.

Inter alia, “surplus” embryos that resulted from in vitro fertilisation and that are no longer intended for parenthood may be used for medical research purposes since then. Since the Amending Act of 2021, embryonic stem cells may also be studied for basic research purposes under strict conditions. Compliance with the comprehensive regulations on embryonic stem cell research as well as the approval of research applications is controlled in France by the Agence de la biomédecine.

United Kingdom
According to the Human Fertilisation and Embryology Act of 1990 embryos may be used for research purposes subject to certain conditions. They may also be created through cell nuclear transfer, i.e. “therapeutic cloning”. These conditions stipulate that the genetic parents must give their consent and that the embryo cannot yet have developed a primitive streak or be older than 14 days. Furthermore, a licence must be granted by the competent regulatory authority, the Human Fertilisation and Embryology Authority (HFEA). Licences are granted on condition that the research project aims to improve infertility treatment or contraception methods, to increase knowledge about the causes of miscarriages or hereditary diseases or to develop methods to identify genetic or chromosomal abnormalities in embryos prior to implantation. With regard to these goals, the project must be without alternative. In addition, a revised version of the Human Fertilisation and Embryology Act 1990 from 2008 aims to ensure, among other things, that all methods of creation and use of human embryos are regulated by the authorities.

As a consequence of the Human Fertilisation and Embryology (Research Purposes) Regulations which came into force on 31 January, 2001, the list of research aims eligible for a licence in conjunction with research using human embryonic stem cells was extended. According to these Regulations, the use and also the creation of embryos for research purposes may also be licensed if the research project aims at improving knowledge of embryonic development or of serious diseases, or at the application of such knowledge to the treatment of serious diseases. A continually updated list of research projects involving human embryonic stem cells that have been licensed to date can be accessed on the HFEA website. In February 2016, the HFEA granted permission for the first time world-wide to researcher Kathy Niakan and her team to make genetic changes to viable embryos.

After the HFEA granted special licences for two research projects in which human-animal hybrids were produced and examined, research on human-animal hybrids in the UK has been permitted since 2008 under the Human Fertilisation and Embryology Act 2008 subject to strict conditions in accordance with the prevailing law.

USA
In the United States, research involving human embryonic stem cells is not as yet explicitly regulated at federal level. Instead, legislative powers in this respect are in the hands of the individual states. However, government influence on research with embryonic stem cells is exerted at federal level insofar as research using public funds is either permitted or prohibited. Private and publicly funded research is thus subject to different regulations. Privately funded research is subject to less stringent regulations and may use embryos specifically created for research purposes.

In 2001, former president George W. Bush had banned the federal funding of research projects involving stem cell lines produced after August 2001. Furthermore, funding was restricted to research on those embryonic stem cell lines produced from ‘surplus’ embryos originally produced for reproductive purposes, following the informed consent of the donor. 

This restriction of state funding to research on older stem cell lines was partially overturned in March 2009 by President Barack Obama. State funding was now also available to scientists who conducted research on newer stem cell lines. The provision that only stem cell lines from ‘surplus’ embryos could be used for research was retained, i.e. it was not allowed to produce embryos for research purposes.

At the end of August 2010, a group of plaintiffs consisting of several Christian organisations and researchers on adult stem cells succeeded in gaining a temporary halt to the financial funding via a preliminary injunction. They argued that current scientific practice demands the destruction of human embryos and that this cannot be supported by the state. At the beginning of April 2011, the decision of the United States Court of Appeal fully lifted the preliminary ban on funding stem cell research with public funds. The lawsuit of the Christian organisations and researchers was therefore unsuccessful. The decision for also financing stem cells research with public funds, was particularly based on the assumption that the research would be able to help millions of seriously ill people and that a ban on research could cause considerable harm to these people.

In 2019, public funding for embryonic stem cell research was restricted under President Donald Trump by prohibiting scientists that were employed by the National Institutes of Health (NIH) from doing research on human fetal tissue derived from voluntary abortions. In addition, an ethics advisory board (The Human Fetal Tissue Research Ethics Advisory Board) was introduced into the NIH approval process for research funding, to be staffed by the US Department of Health and Human Services, which evaluated applications separately. The advisory board stopped its work in September 2020. Furthermore, the restrictions on public funding of stem cell research that were put in place under the presidency of Donald Trump were lifted in 2021 under the presidency of Joe Biden. The other requirements for research projects on embryonic stem cells and their funding remain in place.

Accessible online is a list of projects registered for potential funding at the government agency National Institutes of Health (NIH).

A proven method of the ethical assessment of an action involves on the one hand asking whether the goals pursued with this action are legitimate and on the other hand examining whether the means used to achieve these goals are justifiable.

There is widespread agreement that the goals pursued in research involving human embryonic stem cells, both in fields of basic biological research and therapeutic research, are not only legitimate, but also eminent, i.e. “high-ranking” (cf. Part I: “Medical and Scientific Aspects”). Opinions differ, however, on the question of the justifiability of the means used in this research, if they involve the utilisation and - according to state-of-the-art technology - also the destruction of human embryos.

One manifestation of this disagreement is, for instance, the great diversity of national and international regulatory models and their current discussion (cf. Part II: “Selected national and international laws and regulations”).

The discussion mainly focuses on the question of how far human embryos are particularly worthy of protection and whether their protection status permits using embryos for the derivation of stem cells or even producing them especially for this purpose (1.). Granting a possible inadmissibility of consumptive embryo research leads on to the ensuing question of whether this also applies to ‘surplus’ embryos (2.) or to cell nuclear transfer embryos which are not created by the “conventional” nuclear fusion of two germ cells (3.). Finally, as assessing the justifiability of the means also depends on the availability of other means, the discussion of possible alternatives also plays an important role (4.).

1. The question of the worthiness of protection of the human embryo

The debate about the worthiness of protection of the human embryo is characterised by two different fundamental positions.

At the heart of the first position lies the conviction that from the moment in which nuclear fusion is completed, i.e. right from the beginning, the embryo is entitled to the same protection status as that accorded to human beings after birth on the basis of their personhood. The moral status of the early embryo is thus determined on the basis of the autonomous subject into which he or she may potentially develop. Accordingly, embryos must never be used as mere means to other ends, irrespective of the embryos' developmental stage or how eminent the purposes may be.

Following the second fundamental position, the embryo first needs to reach a specific stage in its development before it is entitled to the same protection status granted to human beings after birth on the basis of their personhood. Prior to this stage, embryos are only entitled to a graduated protection level.

Accordingly, consumptive embryo research using embryos that have not reached the relevant developmental stage requires justification, but is not ruled out entirely on moral grounds. As a consequence, this type of research is not only morally admissible, but is even imperative if the research goals are sufficiently eminent and if there are no alternative means. The same applies to the creation of embryos for research purposes.

Advocates of the first position generally draw on the following lines of reasoning. Firstly, they argue that right from the beginning the embryo has the potential to develop into a person (potentiality argument). What is more, following completion of nuclear fusion the embryo develops into a person in a continuous process. Hence, if one seeks to avoid arbitrary assertions, the commencement of protection worthiness can also only be located at this point in time (continuity and identity argument). Not only that, the proponents of this position point out that it would be a violation of the fundamental principle of human dignity to make worthiness of protection dependent on a property other than that of being a human being (species affiliation argument).

Supporters of the second position, which only accord the embryo full worthiness of protection when it reaches a specific stage of development, vary in their definition of this specific stage. Some consider the moment of nidation in the uterus as the decisive factor, because the embryo would only be truly able to develop from this point onwards. Others define the formation of the primitive streak as the decisive criterion: only then could the possibility of a multiple pregnancy be ruled out and the individuation process was completed. A third group of proponents considers the development of the neuronal preconditions for such capacities as pain sensation or the ability to develop interests to be the decisive factors. They argue that without these capacities it was impossible to establish any claims, even less so to justify any related claims to protection.

The German Embryo Protection Act is based on the first position which prohibits the creation of embryos for research purposes and the use of embryos for purposes other than their preservation. UK regulations - the Human Fertilisation and Embryology Act of 1990 and the Human Fertilisation and Embryology (Research Purposes) Regulations of 2001 - are based on the second position. Under certain further conditions, they not only allow the use of "surplus" embryos for defined research goals up to the formation of the primitive streak, but also the creation of embryos for these very purposes.

2. The question of the admissibility of research involving so-called ‘surplus’ embryos

In many countries where in vitro fertilisation treatments are permitted and carried out, the problem of the so-called "surplus" embryos arises. ‘Surplus’ embryos are embryos created in the course of in vitro fertilisation (IVF), but not transferred to the uterus. They are no longer needed by the parents for a subsequent transfer, either because one of the parents has developed a disease or has died or because the parents do not want to have any more children.

There are two legal options for their use: discarding the embryos or donating them to another couple. A third option being discussed is the use of the embryos by research (such as for the derivation of embryonic stem cells).

Should the use of surplus embryos for the derivation of stem cells and their destruction in this process be permitted?

Supporters of their use for stem cell derivation argue that this does not constitute an inadmissible use as means to an end (an inadmissible “instrumentalisation”). These embryos would not have the chance to develop into a child anyway and are consequently “doomed to die”. The only remaining options were to let them die or store them for an unlimited period.

Opponents have their doubts whether such embryos are necessarily “doomed to die”. They point out the possibility of later embryo adoption. Furthermore, they argue that permitting the use of such ‘surplus’ embryos for stem cell derivation could tempt IVF providers and also IVF users in future to produce even more embryos in order to make them available to research.

Those in favour of such a permission counter that the artificial creation of ‘surplus’ embryos could be prevented by adequate legal regulations. In its statement, the Leopoldina, as a proponent, proposes a control by a federal authority together with an ethics commission in the case of a legalisation of research on surplus embryos. The supporters reject embryo adoption with the argument that it causes a split in parenthood (so-called "split motherhood") since the person who donates the egg is not the same person as the one who will carry the embryo and subsequently will be the social parent. At the same time, this split is associated with considerable risks for the child.

3. The question of the admissibility of research with cell nuclear transfer embryos and their creation

It is hoped that the use of specific cloned stem cells will facilitate the development of multi-faceted, patient-specific therapeutic procedures for previously incurable diseases. The technique for obtaining these stem cells (cell nuclear transfer) as well as the legal provisions governing their use and the relevant ethical debate are discussed in the In Focus section on Research Cloning.

4. The question of the alternatives to human embryonic stem cell research

Given the same goals, means which are ethically less problematic ought to be given priority over ethically more problematic means. In order to be ethically justifiable, the application of means which are ethically more problematic must, therefore, not only be adequate but must also be necessary to achieve the desired goals.

There are critics who doubt that research involving human embryonic stem cells has no alternatives. They believe that the goals of both basic and therapeutic research can also be achieved using tissue-specific adult stem cells. They argue that the derivation of these cells is ethically less problematic. These cells also have the advantage that cell transplants derived from adult stem cells are more likely to be immunotolerant, as these cells are taken directly from the organism of the transplant recipient. However, in the case of embryonic stem cells, the creation of autologous cell transplants is, so the argument goes, only possible by way of “therapeutic cloning”. Furthermore, the critics maintain that transplants produced from adult stem cells show a lower risk of tumour formation and that using adult stem cells has already led to recorded therapeutic successes. This, they point out, has not yet been achieved with embryonic stem cells. Some of the therapeutic procedures developed with adult stem cells have since even become the clinical standard.

The counter argument produced by supporters of research with embryonic stem cells is the fact that adult stem cells seem to have a far lower differentiation potential than embryonic stem cells. The number of various tissue types which can be obtained from adult stem cells, would, therefore, probably be very limited. Apart from this, the argument goes, adult stem cells could not be proliferated on a scale required for the creation of therapeutically efficacious cell transplants. In order to understand better the mechanisms responsible for differentiation, redifferentiation and proliferation, research involving human embryonic stem cells is, therefore from their point of view, absolutely indispensable. Gaining insight into these mechanisms would even be a necessary precondition for the further development of adult stem cell therapies.

Induced pluripotent stem cells have long been considered a beacon of hope for an ethically acceptable alternative to research on human embryonic stem cells. However, concerns have also been raised about their use. On the one hand, it has become apparent that due to epigenetic changes the similarity between embryonic stem cells and induced pluripotent cells is not as close as initially assumed and that the former exhibit a greater susceptibility to mutations. Further information on the current state of research on induced pluripotent stem cells can be found in the Medical and Scientific Aspects section of these In Focus pages. On the other hand, research successes on induced pluripotent cells with the process of tetraploid embryo complementation have raised doubts about the ethical acceptability of this cell type. Tetraploid embryo complementation has made it possible to create viable clones in mouse models with the aid of adult cells and, successively, induced pluripotent cells. Some critics point to the fact that the possibility to derive embryos from iPS cells makes the use of iPS cells ethically comparable to ES cells. In October 2009, the Berlin-Brandenburg Academy of the Sciences (Berlin-Brandenburgische Akademie der Wissenschaften) together with the National Academy of the Sciences (Nationale Akademie der Wissenschaften (Leopoldina)) published a statement concerning this new technique of stem cell derivation. The German Ethics Council published an Ad Hoc Recommendation on this matter in September 2014.

Until now the relatively recent process of transdifferentiation of cells has not appeared to be critical. This process attempts to obtain other specialised cell types (e.g. nerve cells) from differentiated, adult cells (e.g. skin cells) by bypassing stem cells. It is also possible to produce progenitor cells of certain kinds of tissue. For the process of transdifferentiation no embryonic tissue is required. The genetic modifications needed for their production however poses the risk of malignant transformation. More information on the current state of research on transdifferentiated cells can be found in the Medical and Scientific Aspects section of these In Focus pages.

According to advocates of research on embryonic stem cells, this research is indispensable for a deeper understanding of the mechanisms by which human cells differentiate, redifferentiate and multiply. They maintain that gaining insight into these mechanisms is also a vital prerequisite for the further development of alternative stem cell treatments.