SCIENCE POLICY BRIEFING • May 2010

38
Human Stem Cell Research
and Regenerative Medicine
A European Perspective on Scientific, Ethical
and Legal Issues

Contents 5 • Other sources of human embryonic

stem cell-like cells
10 • Statements and recommendations
10 • Future of stem cell research
1 • Foreword 5 • Adult- and tissue-derived in Europe
2 • Introduction stem cells 11 • References
2 • Foetal stem cells 6 • Towards clinical application 13 • List of contributors
4 • Human embryonic stem cells 8 • Ethical and legal issues 14 • Annex 1

Foreword
In 2002 the European Science Foundation (ESF) published
a Science Policy Briefing (SPB) entitled Human Stem Cell
Research: Scientific Uncertainties and Ethical Dilemmas1.
Since then there have been many significant advances in
the field of research, although progress has perhaps been
slower than was originally predicted. During this time, we
have witnessed the emergence of regenerative medicine
(RM), which promises to be one of the most fascinating and
controversial scientific developments of the 21st century.
The possibility of repairing or replacing tissue or organ
function lost due to age, disease, damage or congenital
defects, using human stem cells (hSCs), raises deep ethical
issues, often evoking strong emotions. Clearly, as stated in
2002, scientific research in this field must be undertaken
with a simultaneous consideration of the ethical issues
involved. Thus, the purpose of this policy briefing is to
examine the key scientific questions in hSC research in
the field of RM, examine the current ethical concerns,
particularly as we advance towards clinical application, and
finally analyse how the legislative landscape has altered
in Europe within the previous seven years.
The European Medical Research Councils (EMRC) at
the ESF established a High-Level Expert Group, partly
comprised of members of the previous 2002 Expert Group
but also drawing in other leading researchers, to reflect the
rapidly changing scope of the field. Based on a dedicated
workshop and remote correspondence, these members
made specific recommendations, intended to stimulate
continuing efforts by relevant stakeholders to ensure that
stem cell research is developed into RM applications and Figure 1. A sphere formed by neural progenitor cells differentiated from
the human embryonic stem cell line HS360 in four-week serum-free
other benefits for patients, while at the same time ensuring culture in N2B27 medium. Green immuno-reaction for the marker Map-2,
that the research is conducted in accordance with accepted and red for Nestin.
principles of research ethics. These recommendations Photo by Katja Puttonen, University of Kuopio, Finland. Original magnification × 200.

are summarised at the end of this report. The draft SPB

was presented to the EMRC Standing Committee which
reviewed the report in the wider context of medical research
priorities and the divergent legislation regarding stem cell
research across our Member Organisations. Finally, we
would like to acknowledge and thank the High-Level Expert
Group for their excellent work.

Professor Professor
Liselotte Højgaard Marja Makarow
EMRC Chair ESF Chief Executive

[Link]
Introduction the area of bone and cartilage repair where successful
translation is likely to be achieved first, due in part to
the accessibility of the tissues, their reduced complexity
Stem cell (SC) research holds the promise of treating in comparison to myocardial or neuronal tissues and a
many serious and disabling diseases and disorders high level of concurrent work on new biomaterials for
by replacing damaged, lost or diseased cells through tissue repair.
regeneration. It can be considered part of a new field of There are many different sources of SC, each having
activity that emerged in the early 1990s, rapidly devel- their own advantages and disadvantages. The various
oping over the last decade, and commonly referred to types of SC can be seen in the glossary in Table 1, which
as either tissue engineering or RM. (While RM includes is based upon that devised by Professor Austin Smith,
tissue engineering, it also includes targeted treatments as published in Nature in 20063.
such as gene and small-compound therapies.)
One significant factor that has influenced the course
Transplantation remains today the only possible of hSC research is the ethics surrounding their use4.
therapy for certain terminal organ insufficiencies (liver, It was as a consequence of the strong debate about
heart, lung, kidney). The increase in chronic diseases hSC ethics – reflected in the first SPB published by the
and population ageing has led to an increasing demand ESF on this topic in 2001 – that stimulated concerted
for transplantation, but at the same time the number of efforts on the part of some national governments to
potential donors is decreasing. For many patients, organ find alternative methods using adult SCs, as their use
transplantation represents the only life-saving treatment is considered more acceptable by the general public.
available. There are currently 56 000 patients waiting for In the US for example, the National Institutes of Health
a suitable organ donor in the European Union (EU). (NIH) spent US$3.5 billion on SC research in the period
On 8 December 2008, the European Commission 2005-2008, of which US$260 million was dedicated to
(EC) adopted a proposal for a Directive of the European hESC researchb. This has yielded the remarkable result
Parliament and of the Council on standards of quality of so-called induced pluripotent stem cells (iPS cells)
and safety of human organs intended for transplantation – the reprogramming of adult human cells into ES-like
([Link] cells. The International Society for Stem Cell Research
stance/oc_organs/docs/organs_directive_en.pdf) and (ISSCR) published in December 2008 its “Guidelines for
a ten-point Action Plan for closer co-operation between the Clinical Translation of Stem Cells” ([Link]
Member States on organ donation and transplantation org/clinical_trans/[Link]) partly supported by the
([Link] EUROCORES Programme EuroSTELLS, supported by
stance/oc_organs/docs/organs_action_en.pdf). The the EC, Sixth Framework Programme, under contract no.
Directive and Action Plan address three key challenges: ERAS-CT-2003-980409. These served as a basis for the
(1) improving the quality and safety of organs across publication of the NIH “Guidelines for Human Stem Cell
Europe, (2) increasing organ availability and (3) making Research” released on July 7 2009 (accessible at http://
transplant systems more efficient and accessible. [Link]/policy/[Link]) that have
Even with increased support for research projects in given a new impulse to SC research in the US.
transplantation, there remains an enormous need for RM The value of SC research for RM is significant and
therapies. This is evident, to take only one example, from its value is not only restricted to its direct application
the high number of heart transplantations, 3 500, that towards cell-based therapies, but also in areas such
are undertaken worldwide each year. The number is lim- as the development of hSC-based models of disease
ited by the lack of appropriate donors and the intensive and drug discovery and development. While significant
treatment regimens that are not easy to administer to advances have been made since 2002, including, for
the elderly people who most urgently need transplants. example, understanding how mesenchymal stem cells
Less invasive treatments, such as enabling regeneration (MSCs) impair autoimmunity, with the result that allo-
of damaged heart tissue with SCs, would clearly help to geneic MSCs can be explored in a variety of clinical
alleviate this kind of problem. settings, much remains to be learnt about how to control
Among the numerous potential applications for RM and direct SC fate and function in a patient.
using hSCs are, for example, heart muscle repair following With this paper, the ESF aims to summarise the current
a myocardial infarction, treatment of neurodegenerative scientific and ethical issues that surround hSC research
disorders including Parkinson’s disease, enhancement in RM, review the current legislation landscape in Europe,
of wound repair of the skin, and replacement of dam- and set out the position of the ESF on future priorities
aged bone and cartilage2. In the last decade, research in in this area.
these areas has been translated into early clinical trials
with mixed results, raising hope amongst patients. It is
notable that the first clinical trials using therapy based
on human embryonic stem cells (hESC) were approved
Foetal stem cells
by the Food and Drug Administration (FDA) in the US in
With improved molecular characterisation of various cell
January 2009 for patients with acute spinal cord injury
types, we are obtaining a richer picture of the different
(SCI)a, even though there have been some drawbacks
stem and progenitor cell types residing in the embryo.
with this project more recently. However, it is perhaps in
b. [Link]/news/[Link]
a. [Link] (accessed Apr-19, 2010)

2  |  Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010
For cell therapy purposes, foetal SCs can be derived as unilateral versus bilateral implantation, graft size and
from umbilical cord blood after delivery, or from foetal preparation of donor cells prior to transplantation, make
tissues after termination of pregnancy or spontaneous it difficult to yet draw firm conclusions about the effi-
abortion. There are two types of foetal SCs that are cur- cacy of the transplantations7,8. The feasibility of using
rently of particular medical interest: cord blood SCs and homologous foetal SCs in perinatology for tissue engi-
foetal brain tissue. Cord blood SCs are gaining increased neering in a foetus with a congenital birth defect has
popularity as a cell source in blood cell transplantations, been proposed9. Foetal SCs can also be used in the
as cord blood-derived cells produce fewer cytokines and fields of hepatic cell transplantation10 and heart valve
contain fewer natural killer cells, thus causing less severe tissue re-engineering11.
graft-versus-host disease following transplantation. Safety issues are important when foetal cells are used.
Furthermore, cord blood SCs have a higher prolifera- If rejection and viability of transplanted cells do not seem
tive potential. These features allow a more permissive to be a problem in the central nervous system, concerns
donor-host tissue mismatch and smaller number of cells have been raised regarding potential host-to-graft dis-
to be used, and cord blood is now routinely used for ease propagation. Two subjects with Parkinson’s disease
allogeneic transplantation5. Most of these transplanta- who had long-term survival of transplanted foetal mes-
tions use cord blood from non-profit public cord banks, encephalic dopaminergic neurons for 11 and 16 years,
but a number of private cord banking services have also respectively, presented evidence for Lewy bodies in their
been established to provide patient-specific cord blood grafted neurons. However, the majority of grafted cells
for future use (see also ‘Private companies and per- were functionally unimpaired after a decade, and recipi-
sonal cell banks’ below). Foetal brain tissue obtained ents still experienced long-term symptomatic relief12.
from aborted foetuses has been used in the treatment Non-proven treatments can be dangerous as shown
of Parkinson’s disease as it contains neural progenitor by the case of an Israeli boy who developed multiple
cells. More than 200 patients have already been treated tumours of the central nervous system after receiving
in the US and in Sweden6. In these treatments, several an inappropriate treatment for his ataxia telangiectasia
foetuses are needed to transplant a sufficient number syndrome in Moscow. He was given foetal brain cells,
of cells into one patient. Results of the transplantations which resulted in a severe complication13.
are mixed, and different transplantation strategies, such

Table 1: Glossary with definitions and abbreviations for stem cells and regenerative medicine

Term Abbreviation Definition

Regenerative medicine RM Reconstruction of functionally impaired, diseased or injured tissue by
activation of endogenous repair systems or by implantation of exogenous
cells or combination products.
Tissue engineering An interdisciplinary field that applies the principles of engineering and life
sciences toward the development of biological substitutes that restore,
maintain, or improve tissue function.
Stem cell SC A cell that can continuously produce unaltered daughters and also has
the ability to produce daughter cells that have different, more restricted
properties.
Embryonic stem cell ESC Pluripotent SC lines derived from early embryos before formation of the tissue
germ layers.
Foetal stem cell Foetal SC Found in blood from the umbilical cord, in the placenta or isolated from
aborted foetus.
Adult stem cell Adult SC May be derived from umbilical cord blood or adult tissues, among which bone
marrow and fat are mostly used.
Tissue stem cell A cell derived from, or resident in, a foetal or adult tissue, with potency mostly
limited to that tissue. These cells sustain turnover and repair throughout life in
some tissues.
Induced pluripotent iPS cell An adult somatic cell which is reprogrammed to become pluripotent and
stem cell behave like ESCs typically, by inducing a “forced” expression of certain
genes (including the master transcriptional regulators Oct-4 and Sox2).
Mesenchymal stem cell MSC An adult multipotent cell derived from a well-characterised population that
can form fat cells, cartilage, bone, tendon and ligaments, muscle cells, skin
cells and even nerve cells.

Other abbreviations used for stem cells

Term Abbreviation
Human embryonic stem hESC
cell
Human stem cell hSC

Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010  |  3
 also many differences between the lines16. A second
study, ISCI2, which addressed the culture conditions,
is completed. ISCI3 is underway to explore the genetic
stability of hESCs, as they have a tendency to undergo
genetic alterations during long-term culture.
Many other studies have contributed vast knowledge
of basic biological characteristics of hESCs, their self-
renewal, growth control and optimal culture conditions.
Differentiation protocols have been published for many
cell types including neurons, cardiac muscle cells and
β-cells of pancreatic islets. Basic knowledge about SC
biology may also teach us about the body’s natural heal-
ing capacity and the involvement of an endogenous
pool of SCs that is recruited upon tissue damage17,18.
hESCs may also provide us with good culture systems
to evaluate disease mechanisms19, 20, 21, 22, as well as to
screen – in a high-throughput manner – new compounds
for drug development23,24 which is the current goal of
Figure 2. Non-differentiated human embryonic stem cells growing many biotechnology companies. The UK, for example,
on a feeder cell layer formed by human skin fibroblasts. has set up a public-private consortium “Stem Cells for
Photo by Outi Hovatta, Karolinska Institutet, Sweden. Original magnification × 400.
Safer Medicine” with the long-term objective of develop-
ing a bank of human cell lines derived from hESCs to be

Human embryonic used in early drug discoveryd.

However, using hESCs for therapy, as opposed to their
stem cells use for generating fundamental knowledge or identifying
targets for drug development, is a much greater chal-
lenge for many reasons, including the unpredictability
Derived from early embryos (not only from the inner cell of their self-renewal and differentiation, immunological
mass, but also from the morula, blastomere, or from rejection (as the hESCs are heterologous, i.e. not from
arrested embryos), hESC lines have the potential to form the patient) and the potentially long-term follow up of
any cell or tissue in the body, making them a possible treatment, as the cellular transplants may survive for
source for cell transplantation and tissue engineering many years. However, the results from pre-clinical stud-
(Figures 1 and 2). Since the establishment of the first ies using hESC-derived cells to treat animal models of
hESC line in 199814, a much better understanding of how human diseases have been promising, demonstrating
tissues are generated and maintained has been gained. functional improvement. The first targets have been
This was made possible with the derivation of new hESC disorders with relatively local cell degeneration: SCI25,
lines through the legalised access in certain countries diabetes26 and Parkinson’s disease. The latter has been
to donated surplus eggs following in vitro fertilisation one of the first targets of a new approach, i.e. the gen-
(IVF) treatment. In August 2009, it was estimated that eration of iPS cells (see below)27. Treatments of more
there were approximately 650 hESC lines worldwide and general disorders will take a longer time to achieve. In,
many of these (252 European and 349 non-European) for instance, amyotrophic lateral sclerosis, cell therapy
are registered in the European Human Embryonic Stem using different types of SCs, both pluripotent and tissue-
Cell Registry funded by the European Commission (EC), derived SCs as the cell source, has been extensively
which is not a cell bank but serves as a comprehensive studied28. Nevertheless, moving into a clinical setting
collection of information on hESC lines that have been with human patients is a challenge, with immune rejec-
derived in Europe or are being used in projects based tion being a particular issue.
in the EUc. One long-term goal of the European hESC In summary, understanding the fundamental mecha-
registry website is to provide a platform to compare nisms of self-renewal, pluripotency and differentiation
clinical research results using hESCs across Europe in and creating a reliable characterisation process is critical
a standardised way. if hESCs are to be used as therapeutic tools in RM. Even
One notable project during the last five years has been though other methods are being developed to generate
a common effort to characterise hESC lines, managed hESC lines, including induced (non-embryonic) pluripo-
by the International Stem Cell Forum (ISCF), a 21-mem- tent SCs, at this stage it would be premature to consider
ber organisation (academies, research institutes and limiting any potential avenues of research.
councils, foundations, etc.) established to encourage
international collaboration and funding support for SC
research. Known as the International Stem Cell Initiative 1
(ISCI1), 58 hESC lines from 18 laboratories worldwide
were characterised and shown to have similar expres-
sion patterns for several hESC markers15, but there were
c. [Link] d. [Link]

4  |  Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010
Other sources of human the number of genes required or using alternative gene
delivery systems. Recently, researchers succeeded in
embryonic stem cell-like using just one gene (Oct-4)31, eliminating the need for the
other three genes that were previously required, two of
cells which are known to be potent oncogenes. Although the
virus itself which is used to carry the gene may integrate
into the genomic DNA, thus ruling out the use of viral
Derivation of hESCs by somatic cell vectors in a clinical setting, the results marked another
nuclear transfer (SCNT) step towards the virus-free generation of iPS cells. The
feasibility of deriving human iPS cells free of reprogram-
One possible solution to overcome rejection would be
ming factors by using excisable lentiviruses has been
establishing patient-specific hESC lines by a process
demonstrated. For obvious safety reasons, these human
called somatic cell nuclear transfer (SCNT). This involves
iPS cells represent a more suitable source of cells for
the replacement of the genetic material of an oocyte
modelling human disease32.
with the genetic material from an adult cell. Attempts
have been made in some of the European countries that The use of iPS cells in the treatment of various human
allow this procedure (which are Belgium, Portugal, Spain, diseases would address the immunological and impor-
Sweden and UK), but derivation of hESC lines from the tant ethical challenges that face the use of hESCs.
few embryos established by SCNT in human have not However, there is an immediate need to improve meth-
been successful to date29. One of the drawbacks is the ods to robustly develop these cells before clinical trials
difficulty in obtaining enough donated oocytes for this can even be considered. At this stage it is not possible
purpose. to say whether generating safe iPS cells for cell trans-
plantation in clinical trials will be successful but at the
moment these cells represent a unique route for drug
Reprogramming somatic cells by defined
development and for studying inherited or environment/
factors (induced pluripotent stem cells –
age-related human diseases33.
iPS cells)
One promising alternative to obtaining patient-specific
pluripotent cell lines is by reprogramming somatic cells, Adult- and tissue-derived
which marked a major breakthrough in the field of SC
research (Figure 3). Yamanaka and Takahashi were stem cells
able to reprogram mouse skin cells into SC-like cells,
so called “induced pluripotent stem cells” (iPS cells) by Adult SCs are undifferentiated cells found in a tissue or
transferring four key pluripotency genes (Oct-3/4, Sox2, organ that can differentiate to produce the major spe-
Klf4 and c-Myc) using retroviruses30. By altering the cialised cell types of that tissue or organ. Examples
expression of these genes, skin cells simply dedifferenti- include hematopoietic SCs (HSCs) that give rise to the
ated into pluripotent cells, demonstrating many of the many types of blood cells, including red blood cells,
properties of hESCs; in essence ‘turning back the clock’ macrophages and platelets. The first example of adult
on the adult skin cells. This remarkable discovery has SC-based therapy occurred in 1968 with the successful
opened up a new approach to generating patient-specific completion of the first bone marrow transplant. Since
cells, and since then researchers have been investigat- then the landscape of SC research and its impact on
ing how to improve the technique through a reduction in the treatment options for human diseases has expanded
considerably. Adult SCs offer unprecedented potential
for the treatment of many diseases and disorders such
as Crohn’s disease, graft-versus-host-disease, bone and
cartilage lesions and degeneration, tissue and organ
regeneration, as well as Parkinson’s disease, Duchenne
muscular dystrophy or heart disease. Adult SCs may
be derived from adult tissues such as the skin, adipose
tissue and bone marrow.
Mesenchymal stem cells (MSCs) represent the most
popular type of adult SCs. They can be easily isolated
from various tissues (e.g. bone marrow, adipose and
hepatic tissues, umbilical cord blood) and expanded
in vitro. So far few reports on side effects of clinically
applied MSCs have been published, but MSCs undergo
mutations during culture34 and tumorigenicity is a pos-
sible risk. Some of the preliminary observations have
appeared promising even though the beneficial effects
Figure 3. A round colony of tightly growing human induced of MSC applications were in some studies probably not
pluripotent stem cells on human fibroblast feeder layer. The cells associated with cell replacement and MSC differentia-
have been formed from the parental skin fibroblast line. tion, but with the MSC secretory function that provides
Photo by Outi Hovatta, Karolinska Institutet, Sweden. Original magnification × 100.
indirect trophic effects of the cell therapy35. The mech-

Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010  |  5
anisms of action are still largely unknown, and much clinical grade hESC lines have so far been derived41, but
research remains to be done. the derivation system is not xeno-component free. Xeno-
Adult SCs do not evoke the same ethical concerns as free culture media, feeder cells and feeder-free matrices
using ESCs and are not rejected by the patient’s immune that have been developed are under investigation.
system if originating from an autologous source. However
for certain applications such as neurodegenerative dis- Clinical proof of concept
eases, it may not be possible to obtain autologous SCs
The current clinical status is that while adult SCs of the
of sufficiently good quality for expansion. In such cases,
hematopoietic system – HSCs – are commonly used for
therefore, the use of allogeneic cells may be required, as
bone marrow transplants, other adult SCs are still at an
in organ transplantation, thus raising issues of immuno-
early stage of evaluation in clinical trials. The websites of
suppressive therapy. The emerging field of iPS cells, as
the European Community EudraCT ([Link]
pluripotent cells, may replace tissue-derived stem cells
[Link]/) and of the US NIH ([Link])
in the future in many situations.
provide information on the 107 current clinical trials based
Germinal stem cells have been identified in human on the use of MSCs, the type of adult SC that is expected
testes 36 but their culture, propagation and matura- to reach clinics next. Eight of these trials are in phase III as
tion in vitro are still at an early basic research stage. of April 2010, but only one (just completed) testing the use
This research may add to current standard protocols of MSCs in graft-versus-host-disease involved European
for sperm preservation purposes. Mature sperm and clinical centers, in Italy, UK and Spain. However, European
oocytes have been obtained from mouse ESCs37, 38. involvement is much higher in phase I/II clinical trials, most
Whilst obtaining gametes capable of fertilisation from of these being investigator-driven (not industry-driven) tri-
human SCs is likely to be some way in the future, ongo- als: 25 out of the 82 current phase I/II trials using MSCs
ing research suggests that this could be possible. For are based in 12 different European countries (Belgium,
instance, human early meiotic germ cells have been Denmark, Italy, Germany, the Netherlands, Norway, Spain,
differentiated from hESCs39. UK, France, Finland, Ireland, Slovenia). Therapeutic indi-
cations of ongoing clinical trials using adipose-derived

Towards clinical application SCs include steroid-refractory graft-versus-host disease,

periodontitis, severe chronic myocardial ischaemia, distal
tibia fracture, osteoarthritis, decompensated liver cir-
Various applications of stem cells rhosis, multiple sclerosis, tumour-induced osteomalacia,
vascular diseases, diabetes, fistulising Crohn’s disease,
in regenerative medicine
and several others.
SCs could be applied in RM in various ways, from under- The ESF Forward Look Investigator-Driven Clinical
standing fundamental aspects of SC biology, identifying Trials published in March 2009 (available at [Link]
new compounds for drug development, and perhaps [Link]/idct) made the following recommendations
most appealing for the general public, used as cell-based regarding the conduct of investigator-driven clinical tri-
therapies for many injuries, disorders and diseases. als, most of them being applicable to the field of hSC
research:
GMP compliance – regional/national • Knowledge produced by new biomedical break-
(EU Tissues and Cells Directive) throughs should be fully exploited. This will require
The EU Tissues and Cells Directive (EUTCD)e regulates the creation of sufficient infrastructure for translational
the quality of all cells used in human therapy and requires studies (including tissue and sample banks) and har-
good manufacturing practice (GMP)-based production monisation of regulations for sample storage, sample
systems, which include quality. Regarding hSCs, the shipment and use of biobanks;
quality of the procedures and cleanliness of the prod- • All regulators should use a broad risk-based categori-
ucts have been regulated in this manner, and there are sation of studies, with cell therapy being categorised
additional requirements for hSC-derived cells. If culture as high risk (level D in the proposed categorisation);
constituents contain animal-derived components (e.g. • All procedures and requirements should be adapted
mouse feeder cells or foetal bovine serum), cells can to the appropriate level of risk and include the risk-
absorb animal proteins which are immunogenic and may based approach in the EU Clinical Trials Directive on
promote the rejection of cells after transplantation40. Medicinal Products (2001/20/EC of 4 April 2001)f;
Such substances may also contain infectious agents • The mission and role of ethics committees should be
which are difficult to remove after having been intro- harmonised and the ethical standards of clinical trials
duced exogenously40. Hence, xeno-free culture systems should be increased;
would be optimal in human cell transplantation40. Six • Procedures for submission of clinical trial authori-
sations to the competent authorities should be
e. The EUTCD is made up of three Directives, the parent Directive streamlined across Europe, ideally with only one
(2004/23/EC), which provides the framework legislation, and centralised application;
two technical Directives (2006/17/EC and 2006/86/EC), which
provide the detailed requirements of the EUTCD. Available
from: [Link]
expected_standards_directions.cfm. See also: [Link] f. Available from: [Link]
health/ph_threats/human_substance/legal_tissues_cells_en.htm pharmaceuticals/documents/eudralex/vol-1/index_en.htm
(accessed Apr-19, 2010) (accessed Apr-19, 2010)

6  |  Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010
• Innovative clinical trials should be strongly encour- Safety studies including long-term studies
aged. Specific financial support for GMP production in animals – teratoma formation
of the necessary products should also be part of the
financial support, independent of industry; The major current issue facing the use of hSCs in therapy
• Support should be given to academic institutions act- is that of safety, including questions regarding the epige-
ing as sponsors. Regulatory requirements should be netic status and stability of these cells. A critical issue is
adapted to reflect the risk associated with the study, the risk of teratoma (tumour) formation after transplan-
not its commercial or non-commercial objective; tation of undifferentiated hESCs/iPS cells, which have
• Funding agencies should allow universities, hospitals the ability to form inappropriate tissues. A so-called
and learned societies to conduct solid, multinational, anti-apoptotic gene, termed survivin, contributes to
large-scale investigator-driven clinical studies based teratoma formation by hESCs42. In a previous study,
on the correctly powered scale. For smaller scale rats grafted with hESCs that had been predifferenti-
proof-of-concept studies the funding and structure ated in vitro for 16 days developed severe teratomas,
of organisation of the trials should be adapted appro- whereas most rats grafted with hESCs predifferentiated
priately; and for 20 days or longer remained healthy until the end of
• Funds should be made available not only for clinical the experiment43. This illustrates the need to develop
trials but also for novel add-on biological studies. efficient differentiation protocols based on the genera-
Funding streams for clinical trials should cover all tion of fully differentiated or committed precursor cells.
types, not just medicines. Several strategies can also be used to avoid the trans-
plantation of undifferentiated hESCs, such as sorting
pluripotent cells using GMP-grade flow cytometry, or
Various treatment strategies – autologous
using ‘suicide genes’.
versus heterologous
It is also important to note that not only undifferenti-
For cell therapy, choices have to be made regarding cell ated hESCs could provoke tumour or cancer formation.
type and preparative culture before the therapy begins. A case report shows that even four years after trans-
Each of the different SCs described above have their own plantation of a mix of foetal neural stem cells, a brain
advantages and disadvantages in terms of mechanism tumour appeared44. The theory that tumour cells may
of action and regulation. The most obvious and easiest be damaged versions of normal adult SCs has been
option to implement would be the use of autologous intensively studied. Researchers are still debating which
adult SCs, as these can be harvested from bone marrow cell becomes a tumour cell and tumour SC, but one
or adipose tissue. However, these may have a variable finding45 suggests it is the immature adult SC, at least
capacity to repair tissue, which might be influenced by for certain types of leukemia. Mice whose adult SCs -
the patient’s age and/or gender, the nature of the disease both progenitor and immature – contained a gene that
or concomitant medical treatments. causes leukemia were bred. While the results were not
Another way to obtain autologous SCs is by the gen- conclusive in proving that SCs cause leukemia, they
eration of iPS cells. The potential risk of inappropriate showed that low doses of cancer genes can transform
behaviour such as tumour formation needs to be investi- a SC from something that protects life to something that
gated thoroughly before therapy based on iPS cells can might threaten it. hESCs may also inherently harbour
be considered for clinical trials. features of neoplastic progression46. This highlights
The use of heterologous SCs would offer a logistically the importance of long-term studies to assess clinical
simpler method that could provide, in effect, an “off the treatments.
shelf” product consisting of banked adult SCs or hESCs. The immunogenicity of hESCs is another challenge.
These cells can be much better characterised or even Although autologous tissue-derived cells are ideal in
(genetically) modified before application but might pose this respect, there are many situations where this is just
a risk of rejection. not feasible. Although hESCs have been shown to be
The choice of preparative culture is dependent on the less susceptible to immune rejection than adult cells,
proposed application and on the cell type being used. If this ‘immune privileged’ status has been questioned47
adult SCs are used, it appears feasible to skip the need for and hESCs or their derivatives may be rejected by the
long-term culture and instead prepare and possibly select patient’s immune system. This could be overcome with
cells in the operation room. The cells can then immediately an immunosuppressive regimen, which carries an inher-
be applied without the need for second surgery. As the ent risk, well known in the field of organ transplantation.
risk of cell transformation during culture is excluded, this Other possible options include modulation of the immune
method is much simpler in terms of regulatory approval response, an exciting topic of current research48, or the
and can often be registered as a “medical device” instead generation of patient-specific hESC lines49. Matching
of “Advanced Therapy Medicinal Products” (ATMPs) (see the most suitable existing hESC line for each recipient
‘Transplants’ below). On the other hand if a culture pro- may reduce the need of immunosuppression. Regarding
cedure is used, more extensive characterisation of the iPS cells, another possibility exists. HLA homozygous
product can be done before application, leading to a donor-derived iPS cells would provide unprecedented
better controlled procedure. Regardless of which option cell banking for RM. A calculation has predicted that
is chosen, the clinical outcome and therapeutic index 50 unique iPS cell lines, which are homozygous for the
(efficacy/toxicity) will mostly determine which approach three major HLA loci, would cover 90% of the Japanese
is to be preferred for a specific clinical application. population with a perfect match50.

Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010  |  7
Ethical and legal issues provide models for studying disease development, such
embryos could not under current conditions be used for
therapeutic purposes. More recently, this animal-human
Research (social justice, changes to hybrid approach has been largely superseded by iPS
legislation, human-animal interaction) cell research.
Although technically challenging at the moment, germ
Most scientists are overwhelmed when they review all
cell differentiation from hESC/iPS cells could offer an
relevant regulations and guidelines covering the removal,
unprecedented system to understand the pathologies
storage, use and disposal of secretions, organs and tis-
of infertility and develop new drugs to overcome those.
sues for research applications. In general terms, there
This issue also needs to be discussed from world-level
are a number of key issues that must be addressed
ethical points.
when sourcing human tissues for research use, whether
this is from approved Research Tissue Banks or when
establishing a prospective collection. These cover organs Private companies and personal cell banks
unsuitable for transplantation; samples collected spe- There is increasing interest among private companies
cifically for research, for example blood, other body to create personal cell banks where parents can pay for
fluids or small biopsies; and post mortem material or their child’s umbilical cord blood to be stored for poten-
so-called “surplus tissue” left over from clinical and tial future therapeutic use. Though the use of autologous
diagnostic procedures. The challenge is to be able to SCs procured from umbilical cord blood has immunologi-
work within the regulations and guidelines at a practical cal advantages, it is far from clear whether treatments
level in order to be able to obtain the specific human will be available in the future based on SCs derived from
tissue for research. cord blood. Parents or grandparents may be lured into
In most European countries ethical approval and buying access to personal cord blood banking for their
informed written consent of the patient are requiredg. child or grandchild by attractive advertising and market-
Consent is the central focus of legislation relating to ing methods of private companies. If treatments on the
access to identifiable patient data and use of identifiable basis of cord blood SCs become available there is an
tissue for research. All donors must be fully informed in issue of social justice and social equality with regard to
writing in particular about the aims of the research and personal cord blood banking. Given that such banking is
any potential commercial interest. When sourcing tissues expensive, only a small proportion of the population may
from Research Tissue Banks one has to be sure that be able to buy access to a personal cord blood bank.
the banks are properly licensed, that they have certified Quite apart from these ethical issues, the quality of cord
systems to provide safe tissues with reliable quality and blood conservation needs to be guaranteed.
that the initial informed consent is respected. The banks’
premises, facilities and equipment must be suitable for Transplants (ATMPs)
the storage of human tissues.
“Advanced Therapies” refers to Regulation (EC) No
Generation of human-animal chimeras for research
1394/2007 on Advanced Therapy Medicinal Products
purposes has a long history in science and has been a
(ATMPs)i that will, for the first time, bring all advanced
subject of considerable ethical discussions. Teams in the
therapies (gene, cellular and tissue-based) together
UK obtained permission from the Human Fertilisation and
within a single, integrated European regulatory frame-
Embryology Authority (HFEA) to create animal-human
work, thereby ensuring consistency across Member
hybrid embryos using SCNT. Following the approval of
States. The definition of an ATMP is a “medicinal product
the Human Fertilisation and Embryology Act in October
for human use that is a gene therapy medicinal product,
2008, this technique is now legal in the UK subject to
a somatic cell therapy medicinal product or a tissue
license by the HFEA h. The Human Fertilisation and
engineered product”. The Regulation sets out specific
Embryology Act regulates the creation of a number
technical requirements for these innovative therapies
of types of animal-human hybrids, including “true”
and establishes new standards for clinical trials in the
hybrids, transgenic human embryos and chimeric human
development of advanced medicinal products. Following
embryos. The licences so far issued in the UK are for
the opinion of the European Parliament on 25 April 2007,
the creation of animal-human hybrids which combine an
the Council of Ministers approved the Regulation on
animal oocyte with genetic material from a human adult
advanced therapies in first-reading on 31 May 2007.
cell which would result in a cell with animal mitochon-
The Regulation was translated into all EU official lan-
dria but human nuclear genes51. What happens to such
guages and on 30 October 2007 the Advanced Therapy
mitochondria and how such cells function remains to be
Regulation was formally adopted by the EU Council. The
seen. Evidence suggests that animal-human hybrids do
Regulation was published in the EU Official Journal on 10
not express the genes required for pluripotency51 but
December 2007 and entered into force on 30 December
further research remains to be done. It is clear however,
2007. Soon after the publication of the Regulation, DG
that while such hybrids provide valuable insights into
Enterprise and Industry made public its priorities for the
the fundamental aspects of SC development and may
implementation of the Advanced Therapies Regulation.
The implementation plan has been developed and agreed
g. [Link]
(accessed Apr-19, 2010)
h. [Link] i. [Link]
[Link] (accessed Apr-19, 2010) OJ:L:2007:324:0121:0137:EN:PDF (accessed Apr-19, 2010)

8  |  Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010
with the European Medicines Agency, the EU pharma- of Appeal (EBA, the Supreme Court of the EPO). On 25
ceutical regulatory resource that provides guidance for November 2008, the EBA delivered a long-awaited WARF
newly licensed formulations for human and veterinary ruling62 and affirmed that the EPO will not grant a pat-
use, and whose approval is required for market licensing ent if the invention relies exclusively on a method which
of medicinal products. This public consultation document necessitates the “destruction of a human embryo” from
presents preliminary proposals to replace the existing which the said products are derived. The WARF decision
Part IV of the Annex I to Directive 2001/83/EC. Detailed confirms that this ban stands “even if the said method is
information can be found under: not part of the claims”. The EBA stated that “what needs
[Link] to be looked at is not just the explicit wording of the
apies/docs/consultation-paper-nr_2008-[Link] claims but the technical teaching of the application as a
It remains to be clarified whether SC therapies fit into whole as to how the invention is to be performed”. It fur-
the definition of ATMPs and of “investigational medicinal ther adds that, “to restrict the application of Rule 28(c)…
products” as described in the EU Clinical Trials Directive to what an applicant chooses explicitly to put in his claim
on Medicinal Products: “a pharmaceutical form of an would have the undesirable consequence of making
active substance or placebo being tested or used as a avoidance of the patenting prohibition merely a matter
reference in a clinical trial, including products already of clever and skilful drafting of such claim.”63 According
with a marketing authorisation but used or assembled to the EBA, the WARF decision does not concern the
(formulated or packaged) in a way different from the general question of hSC patentability. In addition, the
authorised form, or when used for an unauthorised indi- EBA rejected the request for a preliminary ruling on the
cation, or when used to gain further information about matter by the European Court of Justice (ECJ) due to
the authorised form”j. lack of any legal and institutional link between the EPO
and the EU.64
Patent situation in Europe With the carefully worded WARF decision, the EBA
has in effect postponed the patent morality issue for
Patenting hESCs at the European Patent Office (EPO) has another few years. It is interesting to see how practices
proved to be a difficult process as national states imple- of the national patent offices will change in view of the
ment different policies on the topic of hESC research. importance of the WARF decision. The UK Intellectual
A patent is a temporary right “to exclude others from Property Office (IPO) has already altered its patenting
making, using, offering for sale, or selling” the inven- practice 65 placing it in line with the EPO. This super-
tion which fulfills specific patentability requirements52 sedes the UK IPO’s previous practice notice and signals
in the specified jurisdiction in return for a disclosure of a significant shift in policy. How this will affect British
the invention. However, having a patent does not give patent policy on hESCs remains to be seen. In addi-
one the right to use the invention, but only to exclude all tion, the pending Brüstle appeal of a German patent
others from the use of the patented invention. A patent (DE 19756864; European Patent EP 1040185) before the
owner is still subject to national laws (such as cloning, German Federal Supreme Court led the Court to refer
embryo research laws, environmental laws, marketing a number of controversial questions to the ECJ in late
regulations, earlier dominating patents, and so forth). 2009. The ECJ is now asked to rule on the “interpreta-
The European Patent Convention (EPC) regulates tion of ‘human embryo’ in the sense of Article 6 of the
the granting of patents53 (examination, issuance) but Biotech Directive; whether a stem cell derived from a
the legal effects (validity, infringement) of a patent fall blastocyst has lost its ability to develop into a human
under national jurisdiction.54 The EPO issues a bundle of still an embryo? If so, is a blastocyst a human embryo? If
national patents55 resulting from a joint application. so, is purely therapeutic use of stem cells a ‘commercial
or industrial purpose’ in the sense of Article 6?” k How
In general, the EPC is not clear on the issue of patenta-
the ECJ addresses these queries has the potential to
bility of hESC technology. Although hESC inventions may
shed light on the issue of patenting biotech applications
fulfill the standard patentability requirements, the EPC
claiming the use of hESCs.
prohibits patentability on ethical grounds for inventions
whose “exploitation or publication would be contrary to Nonetheless, the current EPO approach to patenting
ordre public or morality.”56 The EPO guidelines suggest hESCs in Europe requires a revision to adapt to the fast
that the goal of this morality clause is to “deny protection development of SC technologies, an issue that European
to inventions likely to induce riot or public disorder, or leaders should address quickly.
to lead to criminal or other generally offensive behav-
ior.”57,58 Furthermore, the EPC does not allow patenting Legislation across Europe
on “uses of human embryos for industrial or commercial
In line with one of the recommendations from the previ-
purposes”59.
ous editions of the ESF Science Policy Briefing Human
The past few years of the EPO’s rulings60 have failed Stem Cell Research: Scientific Uncertainties and Ethical
to provide any clear-cut answer to the patentability of Dilemmas, the table of regulations on the use of hSCs in
hESCs, which resulted in many hopes being pinned on
the so-called WARF61 appeal before the Enlarged Board k. Directive 98/44/EC of the European Parliament and of the
Council on the Legal Protection of Biotechnological Inventions
(entered into force on 6 July 1998); The IPKat, Bundesgerichtshof
j. Available from: [Link] refers human stem cell patent case to ECJ (Nov. 2009): http://
pharmaceuticals/documents/eudralex/vol-1/index_en.htm [Link]/2009/11/bundesgerichtshof-refers-human-
(accessed Apr-19, 2010) [Link] (accessed Apr-19, 2010).

Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010  |  9
ESF membership countries was updated (see Annex 1), tries, where such research is not allowed, benefit from
with information on 30 countries includedl,m. In summary, the treatments. This does not mean that patients should
25 countries have adopted legislation which explicitly be denied treatment, but that access to objective infor-
prohibits human reproductive cloning (excluding Poland, mation regarding SC treatment should be made widely
Lithuania and Ireland as well as Croatia and Luxembourg). available for all European citizens.
Seven countries allow hESC research and the derivation
of new hESC lines from supernumerary IVF embryos by
law (Belgium, Sweden, UK, Spain, Finland, the Czech Future of stem cell
Republic and Portugal). The same countries allow SCNT
by law except Finland and the Czech Republic who nei- research in Europe
ther prohibit nor allow it (data not shown in Annex 1).
Three countries have adopted legislation to allow the SC research in Europe has proceeded at a rapid pace
creation of embryos for research purposes under strict over the past decade with a high level of science being
conditions (Belgium, Sweden, UK). Currently, 17 coun- maintained in a field that has become globally competi-
tries allow the procurement of SCs from supernumerary tive66.
embryos, and six countries have not adopted legisla- While the media has tended to make promises to the
tion regarding hSC research (Bulgaria, Croatia, Cyprus, public – including patients – European scientists have
Luxembourg, Romania and Turkey). This ever expanding continued to tread a careful path and act responsibly,
field needs constant updating of legislation and new while making impressive scientific advances. As research
thinking on the ethical questions that arise. For instance, proceeds, it is clear that tissue-derived SCs, hESCs and
there are different ethical aspects to be considered in iPS cells should be studied in parallel. Well-controlled
iPS cell research compared to hESC research. clinical trials are being carried out where appropriate.
As knowledge increases about the safety and function
Access to therapies of different cell types, the promise of the field will hope-
fully start to meet people’s expectations. Legislation
Differing legislation may lead to differences and imbal- relating to the safe use of SCs has been successfully
anced access in Europe to treatments deriving from implemented, and provided that adequate funding is
hESC research. Patients may travel from one country maintained and unresolved issues surrounding patents
to another where they may have access to a treatment are addressed, then there is hope that new treatments
that is forbidden in their own, leading to what could be for many severe diseases could emerge.
considered as an unequal distribution of the benefits SCs offer the opportunity for the revolutionary therapy
and the burdens of SC research. It could be seen as an and medical challenge of the 21st century, a challenge
issue that some countries bear all the burdens of SC that needs to be met by the EU based on ethical prin-
research while patients and inhabitants of other coun- ciples that may differ between European countries, on
respect for human rights both within and outside EU
l. [Link] (accessed Apr-19, 2010)
m. [Link] frontiers, and on the intellectual integrity that has built
(accessed Apr-19, 2010) the identity and democracy of today’s Europe.

Statements and recommendations

• Continued research on all types of SCs derived research opportunities provided that balanced facts
from embryos, foetal tissues and adults remains about the risks and benefits of research are under-
necessary as it is too early to predict their value in stood. If therapies become available, all patients
a specific field. Research using embryonic and iPS across Europe should have equitable access to
cells is required, as the knowledge derived from both such therapies;
is complementary and for the moment the benefits • In view of safety concerns relating to SCs in clinical
and risks are not sufficiently known; applications, chemically defined animal substance-
• While clinical research is clearly important, basic free products and standard operational procedures
research remains essential to understand cellular (SOPs) should be further developed and imple-
differentiation and function; mented. Aspects including proof of functionality,
• The lack of common criteria and universal standards safety, quality control, storage and banking need to
for the preparation of SCs has greatly hampered be addressed before therapy enters the market;
further progress. Furthermore, functional charac- • More studies and information about the immuno-
terisation of SCs is limited by the available methods genicity, epigenetic status and stability of SCs and
for in vitro differentiation. There is an urgent need the immune response of the human organism are
for a comprehensive understanding of SC identity needed; and
and characteristics; • Public funding, including at the European level, is
• Progress toward therapies would be faster if necessary to support the translation and imple-
researchers across Europe were given equitable mentation of SC-based products into the market.

10  |  Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010
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43 Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, industrial or commercial purposes.’
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44 Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, the German Federal Supreme Court.
Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz 61 Wisconsin Alumni Research Foundation G 0002/06.
M, Waldman D, Leider-Trejo L, Toren A, Constantini S, 62 Ibid.
Rechavi G. Donor-derived brain tumor following neural 63 Ibid.
stem cell transplantation in an ataxia telangiectasia 64 Ibid., James Nurton, ‘EPO rulings clarify biotech
patient . PLoS Med. 6(2), e1000029, 2009. protection’ (December 2008) 185 Managing Intellectual
45 Chen W, Kumar AR, Hudson WA, Li Q, Wu B, Property 14-14.
Staggs RA, Lund EA, Sam TN, Kersey JH. Malignant 65 Intellectual Property Office UK, Inventions involving
transformation initiated by MII-AF9: gene dosage and human embryonic stem cell Practice Notice (3 Feb
clinical target cells. Cancer Cell. 13 (5), 432-440, 2008. 2009) [Link]
46 Werbowetski-Ogilvie TE, Bossé M, Stewart M, law/p-pn/[Link] at 19 April
Schnerch A, Ramos-Mejia V, Rouleau A, Wynder T, 2010.
Smith MJ, Dingwall S, Carter T, Williams C, Harris 66 Baker M. Stem cells: Fast and furious. Nature.
C, Dolling J, Wynder C, Boreham D, Bhatia M. 458(7241), 962-965, 2009.
Characterization of human embryonic stem cells with
features of neoplastic progression. Nat. Biotechnol.
27(1), 91-97, 2009.

12  |  Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010
List of contributors This ESF Science Policy Briefing has been
prepared under the responsibility of the Standing
Committee of the European Medical Research
This ESF Science Policy Briefing has been written Councils (EMRC):
by the following contributors:
• Professor Liselotte Højgaard, EMRC Chair,
• Professor Outi Hovatta (Chair), Karolinska Department of Clinical Physiology, Nuclear
Institutet, Huddinge University Hospital, Stockholm, Medicine and PET, Rigshospitalet, University of
Sweden Copenhagen, Denmark
• Professor Dr. Heike Walles (Vice-Chair), • Professor Isabel Varela-Nieto, EMRC Core Group
Department of Tissue Engineering and member, Consejo Superior de Investigaciones
Regenerative Medicine, University of Würzburg, Científicas (CSIC) and CIBERER Instituto
Germany Investigaciones Biomédicas “Alberto Sols”, Madrid,
Spain
• LLD Cand. Amina Agovic, Intellectual Property • Professor Krešimir Pavelič, EMRC Standing
Rights University Center, University of Helsinki, Committee member, Croatian Academy of Sciences
Finland and Art, “Rudjer Boskovic” Institute, Zagreb,
• Dr Philip Avner, Murine Molecular Genetics Unit, Croatia
Pasteur Institute, Paris, France • Dr Carole Moquin-Pattey, Head of Medical
• Dr Andrea Heymer, Department of Tissue Sciences Unit (until 1 September 2009),
Engineering and Regenerative Medicine, University current Head of the Corporate Science Strategy
of Würzburg, Germany Development Unit
• Professor Dr Hans Lassmann, Center for Brain • Dr Stephane Berghmans, Head of Medical
Research, Medical University of Vienna, Austria Sciences Unit (since 1 September 2009)
• Professor Urban Lendahl, Department of Cell and • Dr Fiona Kernan, Science Officer
Molecular Biology, Karolinska Institutet, Stockholm, (until 27 February 2009)
Sweden • Dr Maria Manuela Nogueira, Science Officer
• Professor Frank P. Luyten, Division of (since 1 April 2009)
Rheumatology, Department of Musculoskeletal • Ms Blanche Facchini, Administrator
Sciences, Laboratory for Skeletal Development and
Joint Disorders, Katholieke Universiteit Leuven,
Belgium Acknowledgement:
• Professor Ruud HJ ter Meulen, Centre for Ethics We are extremely grateful to Dr Laurence Lwoff,
in Medicine, University of Bristol, United Kingdom Head of the Bioethics Division at the Council of Europe
• Professor Gerjo JVM van Osch, Department (Strasbourg, France) who carefully and critically
of Orthopaedics and Department of reviewed this document on all ethical aspects.
Otorhinolaryngology, Erasmus MC, University The initiative for and the development of this
Medical Center, Rotterdam, The Netherlands Science Policy Briefing have been coordinated by
• Professor Flora de Pablo, Consejo Superior Dr Fiona Kernan, former Science Officer,
de Investigaciones Científicas (CSIC), Centro de Dr Maria Manuela Nogueira, Science Officer, and
Investigaciones Biológicas, Madrid, Spain Dr Carole Moquin-Pattey, former Head of the Medical
• Professor Bogdan Petrunov, National Center of Sciences Unit, European Science Foundation, France.
Infectious and Parasitic Diseases, Sofia, Bulgaria
• Professor Miodrag Stojkovic, Spebo Medical,
Leskovac and Human Genetics, Medical School,
University of Kragujevac, Serbia

Science Policy Briefing 38 – Human Stem Cell Research and Regenerative Medicine – May 2010  |  13
Annex 1: Human stem cell regulations and legislation in Europe (May 2010)

Country Repro­ductive Research authorised by national law on Prohibition No specific Ministry or official body
cloning of human legislation in charge
prevented by Stem cells * Human embryos Aborted embryonic regarding
national law foetuses stem cell hESC
Procurement of stem Creation of human
cells from super­ embryos for research (hESC) research
numerary embryos purposes ** research

Austria 1,2 • • Federal Chancellery

Belgium • • • Public Health & Research (W)

Justice & Health (F)
Bulgaria 3,4 • • Health

Croatia 3,4 • N/A

Cyprus3,4 • • Independent Body

Czech • • Health
Republic 3,4

Denmark 3 • • Science Technology and Innovation

Estonia 3,4 • • Social Affairs

Finland • • • Social Affairs and Health

France • • • Health

Germany • • Federal Ministry of Health

Greece 3,4 • • Development and Health

Hungary 3,4 • • • Health

Iceland 3,4 • • Health and Social Security

Ireland • Department of Health and Children

Italy • • • Health

Lithuania 1,3,4 • Health

Luxembourg 6 • Health

The • • • Health, Welfare and Sports

Netherlands
Norway 3 • • • Health and Care Services

Poland 1 • Health and Social Affairs & National

Education and Science
Portugal 3,4 • • Health

Romania 3,4 • • Health

Slovakia 1,3,4 • • • Health

Slovenia 3,4,7 • • • Health

Spain 3,4 Health & Science and Innovation

• • •
Sweden 8 Health and Social Affairs & Education
• • • •
Switzerland 3,4
• • Federal Office of Public Health

Turkey 3,9 • • Health

United • • • • Department of Health

Kingdom

* P rohibiting the procurement of stem cells from supernumerary embryos but allowing the import and use of stem cell lines. 2. AT: The Austrian Bioethics Commission published an opinion on 16 March 2009 which recommends allowing hESC
** SCNT is not considered in this table: Belgium, Sweden, UK, Spain and Portugal allow SCNT by law, while Finland and the derivation from supernumerary IVF embryos.
Czech Republic neither prohibit nor allow it by law. 3. C ountries who have signed and ratified the 1997 Convention of the Council of Europe on Human Rights and Biomedicine
1. C ountries that voted against the Council Decision on hESC research during FP7 ([Link]/ueDocs/ CETS 164 ([Link]
cms_Data/docs/pressData/en/intm/[Link]) 4. C ountries who have ratified the 1998 Protocol on the Prohibition of Cloning in Human Beings CETS 168 ([Link]
[Link]/Treaty/en/Treaties/Html/[Link])
Specific national committee(s) Competences of the committee members Committee website(s)

Bioethics Commission Medical experts (reproductive medicine, gynaecology, psychiatry, [Link]/DesktopDefault.

oncology, pathology), legal experts, sociologists and experts aspx?TabID=3575&Alias=english
in philosophy, theology and microbiology.
Advisory Committee on Bioethics 5 Biologists, ethicists, lawyers, philosophers, physicians and [Link]
theologians. pageid=56,512676&_dad=portal&_schema=PORTAL
Central Ethical Committee 5 Medical doctors, pharmacist, pharmacologist and laywer. Not available

N/A N/A N/A

National Bioethics Committee Biologist, geneticist, medical doctor, psychologist and sociologist. [Link]

(a) Bioethical Commission of the R & D Council and Bioethicist, biologist, biotechnologist, ethicists, geneticist, immunologist, [Link]/[Link]?idsekce=15908
(b) Ethical Committee of the Ministry of Health 5 medical scientist, molecular biologists, philosophers, physiologist,
sociologist and theologian.
Council of Ethics 5 Bishop, former politician, journalist, lawyer, lay persons, scientists, [Link]/[Link]
teacher, theologian and vicar.
Council on Bioethics Ethicists, lawyers, medical doctors and ministry representatives. [Link]

Sub-committee on Medical Research Ethics of the Ethicists, medical doctors, lawyers and lay persons. [Link]/e/[Link]
National Advisory Board on Health Care Ethics 5
Biomedicine Agency 5 Lay persons, philosophers, theologians, scientists and medical [Link]
doctors.
(a) German National Ethics Council (Deutscher (a) Scientists, politicians, lawyers, lay persons, philosophers, [Link]
Ethikrat) and (b) Central Ethics Commission for Stem medical experts, bishop and theologians and (b) biologists, ethicists, [Link]/cln_049/nn_216782/EN/Content/Institute/
Cell Research 5 medical experts and theologians. DepartmentsUnits/StemCell/StemCell__node.html?__
nnn=true
National Bioethics Commission Lawyers, philosophers, scientists and theologians. [Link]/[Link]?category_id=3

Health and Scientific Council/National Scientific and Bioethicist, biologist, geneticist, lawyer, lay person, medical doctors, [Link] (in Hungarian only)
Ethical Committees 5 nurse and priest.
National Bioethics Committee Lawyers, medical doctors, philosophers, scientists and theologians. [Link]

Irish Council for Bioethics 5 Ethicists, lawyers, scientists, philosophers and physicians. [Link]/

National Bioethics Committee 5 Ethicists, lawyers, medical doctors, scientists, pharmacologists and [Link]/bioetica/eng
patient representative.
Bioethics Committee Ethicist, geneticist, lawyer, medical doctors, philosophers, [Link]
psychologists, psychiatrist and priest.
(a) National Consultative Bioethics Commission for Government representative (Social Security), lawyers, [Link]/
Health and Life Sciences and (b) Committee for medical doctors, social workers, teachers and theologians.
Research Ethics (Ministry of Health)
Central Committee on Research Involving Human Ethicists, medical doctors, nurses, scientists and pharmacologists. [Link]
Subjects 5
National Committee for Medical and Health Ethicists, lawyer, lay persons, pharmacist, philosopher and [Link]/In-English/
Research Ethics 5 psychologist.
N/A N/A N/A

(a) National Committee for Reproductive Medicine (a) Biologists and medical doctors and (b) geneticists, legal experts, [Link]/cnecv/en/
and (b) National Council of Ethics for the Life medical doctors, philosophers and theologians.
Sciences 5
Bioethics Commission of Health and Family N/A N/A

National Ethics Committee Geneticist, medical doctor, ministry representative (Health), priest, [Link]
sociologist and theologian.
(a) National Committee for Medically Assisted (a) Ethicist, lawyer, medical doctor, ombudsman representative and Not available
Reproduction and (b) National Medical Ethics psychologist and (b) ethicist, lay person, lawyer, physicians, psychologist,
Committee sociologist and theologian.
(a) National Commission on Human Reproduction Scientists, lawyers, psychologists and government representatives Not available
and (b) Observatory of Law and Ethics (Health).
National Council on Medical Ethics Ethicists, lawyer, medical doctors, politicians and ministry representative [Link]
(Health and Social Affairs).
National Advisory Commission on Biomedical Ethicists, lawyers, lay persons, medical doctors and scientists. [Link]
Ethics 5 [Link]/nek-cne/
Ethics Council 5 Medical doctors, a pharmacist, and ministry representatives (Health). Not available

(a) Human Fertilisation and Embryology Authority Ethicists, journalist, lawyers, lay person, medical doctors and scientists. [Link]
and (b) Human Genetics Commission 5 [Link]

5. A part from national committee(s), whether existing or not, there are local and/or regional ethical committees. 7. S I: Research on supernumerary embryos from IVF procedures (and thus the procurement of hESC) is allowed with zygotes
6. L U: A new law is under preparation. Opinion against human reproductive cloning has been given in 2004. Opinion for the or embryos until 14 days of development.
authorisation of research on stem cells obtained from supernumerary embryos and of creation of embryos for therapeutic 8. S E: Tissue from aborted fetuses may be used for medical purposes only.
purposes has been given in 2003. 9. T K: hESC research has been suspended at all levels by the Turkish Ministry of Health and legislation regarding hESC
research is under preparation.
The European Science Foundation (ESF) was established in 1974 to provide a common platform for its Member Organisations
to advance European research collaboration and explore new directions for research. It is an independent organisation,
owned by 79 Member Organisations, which are research funding organisations and research performing organisations,
academies and learned societies from 30 countries. ESF promotes collaboration in research itself, in funding of research
and in science policy activities at the European level.
ISBN: 978-2-918428-12-1
Print run: 1 000 – May 2010

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