Report on human embryonic stem cell research

Brussels, 7 April 2003

Executive summary

Background:

Stem cell research is one of the promising areas of biotechnology, which offers the prospect of developing new methods to repair or replace tissues or cells damaged by injuries or diseases and to treat serious chronic diseases, such as diabetes, Parkinson's, chronic heart failure as well as stroke and spinal cord injuries.

Stem cell research is expected to be equally important for basic science to understand cell differentiation and growth as well as for other specific medical applications such as for the understanding of disease development and for the development of safer and more effective drugs. Scientists are intensively studying the fundamental properties of stem cells.

Report on Human Embryonic Stem Cell Research (Commission staff working paper) - 454kB

One of the possible sources for stem cells is human pre-implantation embryos. However, when this research involves the use of human embryos it raises the question of ethical values at stake and of the limits and conditions for such research.

The complexity of this issue with its ethical implications has been highlighted in the process of adoption of the Sixth Framework Programme for Research (FP6) and its implementing Specific Programmes, where the specific issue of human embryonic stem cell research was subject to debate.

In the 6 th Framework Programme, Community stem cell research funding is foreseen under Priority 1 " Life Sciences, Genomics and Biotechnology for human health ", section i "Application of knowledge and technologies in the fields of genomics and biotechnology for health". In particular, "research will focus on…development and testing of new preventive and therapeutic tools, such as somatic gene and cell therapies (in particular stem cell therapies)" (1) .

Pending the establishment of detailed implementing provisions by end 2003 at the latest, the Commission agreed however not to fund during this period research projects involving the use of human embryos and human embryonic stem cells with the exception of projects involving banked or isolated human embryonic stem cells in culture. The Commission stated its intention of presenting to Council and European Parliament a report on human embryonic stem cells, which would form the basis for discussion at an inter-institutional seminar on bioethics (2) .

The present report is the result of this commitment, and aims to provide a description of the state of play of the scientific, ethical, legal, social and economic issues related to human stem cell research and human embryonic stem cell research.

The purpose of the report is to provide a basis for an open and informed debate at the above-mentioned inter-institutional seminar (3) .

Taking into account the seminar's outcome, the Commission will submit a proposal establishing further guidelines on principles for deciding on the Community funding of research projects involving the use of human embryos and human embryonic stem cells.

The content of the report:

Characteristics of human stem cells

Stem cells have three characteristics that distinguish them from other types of cells:

• they are non-differentiated (unspecialised) cells,

• they can divide and multiply in their undifferentiated state for a long period.

• under certain physiological or experimental conditions, they can also give rise to more specialised differentiated cells such as nerve cells, muscle cells or insulin producing cells etc.
Stem cells are found in the early embryo, in the foetus and the umbilical cord blood, and in many tissues of the body after birth and in the adult. These stem cells are the source for tissues and organs of the foetus and for growth and repair in the new born and adult body. As development proceeds beyond the blastocyst stage (5-7 days after fertilisation), the proportion of stem cells decrease in the various tissues and their ability to differentiate into different cell types also decrease at least when they are situated in their natural environment.

Classification of human stem cells

In this report a distinction is made between three groups of stem cells, referring to their origin and method of derivation:

• Human embryonic stem cells, which can be derived from a preimplantation embryo at the blastocyst stage.

• Human embryonic germ cells, which can be isolated from the primordial germ cells of the foetus.

• Human somatic stem cells, which can be isolated from adult or foetal tissues or organs or from umbilical cord blood.
Potential application of human stem cell research

Transplantation of haematopoïetic stem cells (from bone marrow, peripheral blood or umbilical cord blood of a healthy donor) has been used for more than a decade to treat e.g. haematological malignancies such as leukemia or congenital immuno-deficiencies. Autologous transplantation (transplantation of stem cells from the patient's own bone marrow or peripheral blood) was introduced to rescue the bone marrow of patients who had received high dose of chemotherapy. It is now increasingly being used as primary treatment of other types of cancer such as breast cancer and neuroblastoma. Autologous stem cell transplantation is also used experimentally to treat difficult auto-immune conditions and as a vehicle for gene therapy. Today, over 350 centres in Europe are performing more than 18 000 bone marrow transplants a year (4) .

Novel stem cell based therapies (often called regenerative medicine or cell based therapies) are also being investigated to develop new methods to repair or replace tissues or cells damaged by injuries or diseases and to treat serious chronic diseases, such as diabetes, Parkinson's, chronic heart failure or stroke and spinal cord injuries. Stem cell research is expected to be equally important for basic science as well as for other specific medical applications.

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• For the development of novel stem cell based therapies. Three therapeutic concepts are currently being envisaged:
  • Transplantation of differentiated cells derived from stem cells: Stem cells may be grown and directed to differentiate into specific cell types in the laboratory and then be transplanted (e.g. insulin producing cells to treat diabetes, heart muscle cells to treat heart failure or dopamine producing neurones to treat Parkinson's disease etc...) The source for the specific differentiated cell types could be embryonic or somatic stem cells, including the patient's own stem cells.

  •  Direct administration of stem cells: In some cases it may be possible and/or necessary to administer stem cells directly to the patient in such a way that they would colonise the correct site of the body and continuously differentiate into the desired cell type (e.g. systemic "Homing").

  •  Stimulation of endogenous stem cells: The possibility that self-repair could be induced or augmented by stimulating an individual's own population of stem cells for example by administrating growth factors is also being explored.

These novel stem cell based therapies are still at their very early stage of development. In particular regarding the transplantation of differentiated cells derived from stem cells, several scientific and technical hurdles needs to be resolved before clinical application of these therapies, including

• Understanding of the mechanisms regulating stem cell growth, fate, differentiation and dedifferentiation.

•  Eliminating the risk of development of inappropriate differentiated cells and cancerous cells. The risk of tumorigenicity has in particular been highlighted concerning the use of human ES cells as these stem cells develop teratomas.

•  Ensuring the function and viability of the stem cells or their derivatives during the recipient's life.

•  Overcoming the problem of immune rejection (which does not arise in the case where the patient's own stem cells can be used).

For the generation of human cells lines to be used in drug development at pre-clinical stage and in toxicology. Normal human cell types generated from human stem cells can be genetically or pharmacologically manipulated and used for drug discovery. These cell lines may provide more clinically relevant biological systems than animal models for drug testing and are therefore expected to contribute to the development of safer and more effective drugs for human diseases and ultimately to reduce the use of animals. They also offer the possibility to develop better in vitro models to enhance the hazard identification of chemicals. It is possible that these applications will turn out to be the major medical impact of human ES cell research at least in a short-term perspective, as the problems of immune rejection, viability and tumorigenicity do not apply here.

For the understanding of human development. Human ES cells should offer insights into developmental events that cannot be studied directly in the intact human embryo but that have important consequences in clinical areas, including birth defects, infertility, and pregnancy loss.

For the understanding of the basic mechanisms of cell differentiation and proliferation. The understanding of the genes and molecules, such as growth factors and nutrients, that function during development of the embryo may be used to grow stem cells in the laboratory and direct their development into specialized cell types. Some of the most serious medical conditions, such as cancer, are due to abnormal cell division and differentiation. A better understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapies.

The current advantages and limitations of human embryonic and somatic stem cells and the needs regarding the derivation of new human embryonic stem cell lines

In light of the current state of knowledge, human embryonic and somatic stem cells each have advantages and limitations regarding their potential uses for basic research and novel stem cell based therapies.

It is a matter of debate within the scientific community whether human embryonic stem cells have a greater potential than human somatic stem cells (isolated from foetal or adult tissue). Currently, human ES cells are of particular interest because they have the potential to differentiate into all cell types in the body (they are pluripotent). The recent reports (5) indicating that somatic stem cells may have a greater potential for differentiation into different cell types than previously thought (for example bone marrow stem cells under certain experimental conditions may differentiate into neurones, skeletal and cardiac muscle cells), have opened up the question whether research on human embryonic stem cell is needed and ultimately whether the derivation of new human embryonic stem cell lines may be obsolete at this stage. In spite of the optimism generated by the recent research reports on the pluripotentiality of human somatic stem cells, many scientists, including those who conduct somatic stem cell research, support the continuation of human embryonic stem cell research, and do not support the limitation of research to somatic stem cell research only (6) .

The conclusions of many reports (7) have highlighted that it is too early to know what important findings will come from embryonic or somatic stem cell research and which stem cells will best meet the needs of basic research and clinical applications.

Several arguments have been put forward regarding the needs for derivation of new human embryonic stem cell lines.

In particular that human embryonic stem cell research has only just begun and scientists do not yet know if they have developed the best procedures for isolating or maintaining human ES cells in culture. It has also been reported that many of the existing embryonic stem cell lines have been patented in the US. This could create a position of dependence from private industry in other parts of the world (8) .

Governance of human stem cell research

Human embryonic stem cell research raises complex ethical questions. The question whether it is ethically defensible to do research on embryonic stem cells can be described as a conflict between different values, between different actors' rights and obligations, or between the short- and long-term interests of different groups. On the one hand, there is interest in new knowledge that can lead to treatment of hitherto incurable diseases. On the other hand, when this research involves the use of human embryos, it raises the question of ethical values at stake and of the limits and conditions for such research (9) . Opinions on the legitimacy of experiments using human embryos are divided according to the different ethical, philosophical, and religious traditions in which they are rooted. EU Member States have taken very different positions regarding the regulation of human embryonic stem cell research. It confirms that different views exist throughout the European Union concerning what is and what is not ethically defensible.

Ethical issues at stake:

As highlighted in the opinion n° 15 of The European Group on Ethics in Sciences and New Technologies regarding " Ethical aspects of human stem cell research and use", issued 14 November 2000, (10) the following fundamental ethical principles are applicable to human embryonic stem cell research:

• The principle of respect for human dignity.

• The principle of individual autonomy (entailing the giving of informed consent, and respect for privacy and confidentiality of personal data).

• The principle of justice and of beneficence (namely with regard to the improvement and protection of health).

• The principle of freedom of research (which is to be balanced against other fundamental principles).

• The principle of proportionality (including that research methods are necessary to the aims pursued and that no alternative more acceptable methods are available).

In addition, the EGE considers it important to take into account, based on a precautionary approach, the potential long-term consequences of stem cell research and use for individuals and the society."

Concerning the creation of embryos for research purpose the EGE considered that "the creation of embryos for the sole purpose of research raises serious concerns since it represents a further step in the instrumentalisation of human life" and deemed " the creation of embryos with gametes donated for the purpose of stem cell procurement ethically unacceptable, when spare embryos represent a ready alternative source" .

Furthermore the EGE considered "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 spare embryos, foetal tissues and adult stem cells ".

Concerning the ethical acceptability of human embryonic stem cell research in the context of the Community Framework Programme, the EGE concluded that "//… there is no argument for excluding funding of this kind of research from the Framework Programme of research of the European Union if it complies with ethical and legal requirements as defined in this programme".

Secondly the EGE stated, that:

"Stem cell research based on alternative sources (spare embryos, foetal tissues and adult stem cells) requires a specific Community research budget. In particular, EU funding should be devoted to testing the validity of recent discoveries about the potential of differentiation of adult stem cells. The EU should insist that the results of such research be widely disseminated and not hidden for reasons of commercial interest."

The EGE identified the following principal requirements regarding human embryonic stem cell research and the procurement of embryonic stem cells from supernumerary embryos:

• Free and informed consent from the donating couple or woman.

• Approval of the research by an authority.

• No financial gain for donors.

• Anonymity of the donors and protection of the confidentiality of personal information of the donors.

• Transparency regarding research results.

Concerning clinical research the EGE stressed the importance of:

• Free and informed consent of the patient.

• Risk-benefit assessment.

• Protection of the health of persons involved in clinical trials.

Regulation of human embryonic stem cell research in EU Member States (11)

EU Member States have taken different positions regarding the regulation of human embryonic stem cell research and new laws or regulations are being drafted or debated. Taking into account the situation, as of March 2003, the following distinctions can be made:

• Allowing for the procurement of human embryonic stem cells from supernumerary embryos by law under certain conditions: Finland, Greece, the Netherlands, Sweden and the United Kingdom.

• Prohibiting the procurement of human ES cells from supernumerary embryos but allowing by law for the import and use of human embryonic stem cell lines under certain conditions: Germany. The import and use of human ES cell lines is not explicitly prohibited in e.g. Austria, Denmark and France and authorisation is still being discussed.

• Prohibiting the procurement of human ES cells from supernumerary embryos: Austria, Denmark, France, Ireland and Spain. The legislation in Spain only allows the procurement of human ES cell from non-viable human embryos under certain conditions.

• No specific legislation regarding human embryo research or human ES cell research: Belgium, Italy, Luxembourg and Portugal.

• Allowing by law for the creation of human embryos for research purposes: UK is for the moment the only Member State, which allows by law for the creation of human embryos either by fertilisation of an egg by a sperm, or by somatic cell nuclear transfer (SCNT, also called therapeutic cloning) for stem cell procurement. The bill under discussion in the Belgian Parliament would allow for the creation of human embryos for research purposes including by SCNT. The Dutch Embryo Act of 2002 includes a five-year moratorium for the creation of embryos for research purposes including by SCNT.

• Prohibiting the creation of human embryos for research purposes and for the procurement of stem cells by law or by ratification of the Convention of the Council of Europe on Human rights and Biomedicine signed in Oviedo on 4 April 1997: Austria, Denmark, Finland, France, Germany, Greece, Ireland, Netherlands, Portugal and Spain.

New regulations under discussion in EU Member States:

Belgium: A bill on research on human embryos in vitro was approved by the Belgian Senate in 2002 and it is now under discussion in the Parliament. The draft legislation proposes to authorise the procurement of embryonic stem cells from supernumerary embryos under certain conditions, and to create a "Federal Commission for scientific medical research on embryos in vitro ".

Denmark: A revision of the current legislation to allow for the procurement of human ES cells from supernumerary embryos is under discussion.

France: A revision of the Bioethics Law of 1994 has been approved by the Senate in January 2003 and should be discussed by the Parliament in the first semester of 2003. It proposes to allow research on supernumerary human embryos including the procurement of human ES cells for 5 years under certain conditions. A central authorizing body will be created.

Italy : a law on in vitro fertilisation is under discussion.

Portugal: A committee has been established in Portugal for the preparation of a law on human embryo and human ES cell research.

Spain: A revision of the current legislation is under discussion.

In 1998 the National Committee for Human Artificial Reproduction was created. In its second opinion, delivered in 2002, it advised to conduct human embryonic stem cell research using as a source supernumerary embryos, estimated in Spain to be over 30 000.

The Ethics Advisory Committee for Scientific and Technological Research was established in April 2002 and gave in February 2003 its first opinion on research on stem cells. It recommended to the government that research on both adult and embryonic stem cells should be implemented; that the legislation should be modified to allow the isolation of human embryonic stem cells from supernumerary embryos.

Sweden: A revision of the current legislation is under discussion. The Parliamentary Committee on Genetic Integrity proposed, in their report published 29 January 2003, not to implement a general prohibition against producing fertilised eggs for research purposes. It should also be noted, however, that in the view of the Committee the creation of embryos by transfer of somatic cell nuclei (so called therapeutic cloning) should be treated in the same way and thus in principle be allowed.

Regulations in countries acceding to the EU

Cyprus, Czech Republic, Estonia, Hungary, Lithuania, Slovak Republic, Slovenia have ratified the Convention of the Council of Europe on biomedicine and human rights.

Concerning the countries acceding to the EU, no specific regulations regarding human embryonic stem cell research have at present been implemented. Estonia, Hungary, Latvia, Slovenia have implemented legislation authorising research on human embryos under certain conditions. In Lithuania, Poland and the Slovak Republic human embryo research is prohibited. No specific regulation regarding embryo research exist in Cyprus, Malta and the Czech Republic. A bill is under preparation in Czech Republic.

Governance of stem cell research in the context of FP6

As stated in the Treaty of the European Union, article 6:

"1. The Union is founded on the principles of liberty, democracy, respect for human rights and fundamental freedom, and the rule of law, principles which are common to the Member States.

2. The Union shall respect fundamental rights, as guaranteed by the European Convention for the protection of Human Rights and Fundamental Freedoms signed in Rome on 4 November 1950 and as they result from the constitutional traditions common to the Member States, as general principles of Community law.

3. The Union shall respect the national identities of its Member States.

4. The Union shall provide itself with the means necessary to attain its objectives and carry through its policies."

In accordance with the EU Treaty, each Member State retains its full prerogative to legislate on ethical matters. At the level of the Community, ethical principles have been defined with regard to the funding of research under the research Framework Programme.

As far as FP6 is concerned, the following ethical principles have been established (12) :

• "Fundamental ethical principles are to be respected. These include the principles reflected in the Charter of fundamental rights of the EU including the protection of human dignity and human life…"

• "… in accordance with Community law"

• "…in accordance with legislation, regulations and ethical guidelines in countries where the research will be carried out."

• "The following fields of research shall not be financed under this programme:
  • research activities aiming at human cloning for reproductive purposes

  • research activity intended to modify the genetic heritage of human beings which could make such change heritable (13)

  • research activities intended to create human embryos solely for the purpose of research or for the purpose of stem cell procurement, including by means of somatic cell nuclear transfer (often referred to as therapeutic cloning).

… funding of research activities that are prohibited in all the Member States is in all circumstances excluded."

"In compliance with the principle of subsidiarity and the diversity of approaches existing in Europe, participants in research projects must conform to current legislation, regulations and ethical rules in the countries where the research will be carried out.

In any case, national provisions apply and no research forbidden in any given Member State will be supported by Community funding in that Member State.

Where appropriate, participants in research projects must seek the approval of relevant national or local ethics committees prior to the start of the RTD activities. An ethical review will be implemented systematically by the Commission for proposals dealing with ethically sensitive issues, in particular proposals involving the use of human embryos and human embryonic stem cells".

As stated in the Council minutes of 30 September 2002 (14) " The Council and the Commi s sion agree that detailed implementing provisions concerning research activities involving the use of human embryos and human embryonic stem cells…shall be established by 31 December 2003.

The Commission will during that period…not propose to fund such research, with the exception of banked or isolated human embryonic stem cells in culture ".

Socio-economic aspects

While many of the demonstrations of the potential of stem cell research have arisen from academia, the development of this potential i.e. into therapeutic products requires industrial and commercial inputs. For example, industrial involvement will be needed for large scale and good manufacturing production of cell lines, to support multicentre clinical trials, marketing, distribution etc.

In 2001 about 30 public and private biotechnology firms were doing stem cell research and about a dozen are currently investigating the potential of both somatic and embryonic stem cells. Few, if any, companies are investing solely in human embryonic stem cell research.

.htm">http://www.parliament.the-stationery-off ice.co.uk/pa/ld200102/ldselect/ldstem/83 /8301.htm Swedish National Council of Medical Ethics: statement of opinion on embryonic stem cell r e search, 17.01.2002, HYPERLINK http://www.smer.gov.se/ http://www.smer.gov.se/
(8) The Health Council of the Netherlands report on 'Stem cells for tissue repair. Research on the r apy using somatic and embryonic stem cells' June 2002. http://www.gr.nl/pdf.php?ID=429
(9) Annex E - Opinion No. 15 of the European Group on Ethics regarding the Ethical aspects of h u man stem cell research and use . http://europa.eu.int/comm/european_group_ethics/index_en.htm
(10) Annex E - Opinion No. 15 of the European Group on Ethics regarding the Ethical aspects of h u man stem cell research and use . http://europa.eu.int/comm/european_group_ethics/index_en.htm
(11) European Commission, DG Research, Directorate E: Survey on opinions from National Ethics Committees or similar bodies, public debate and national legislation in relation to human embr y onic stem cell research and use (last update March 2003) Survey on the National Regulations in the European Union regarding Research on Human E m bryos - B. Gratton - published by the Secretariat of the EGE - European Commission - July 2002
(12) OJ L 232 of 29.8.2002,p.4 OJ L 294 of 29.10.2002, p. 8.
(13) Research relating to cancer treatment of the gonads can be financed.
(14) Annex F.

DN: MEMO/03/81 Date: 07/04/2003