Progress in Neurobiology 110 (2013) 63–73

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Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

Scientific and ethical issues related to stem cell research and interventions in
neurodegenerative disorders of the brain
Roger A. Barker a,*, Inez de Beaufort b,1
a
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site Robinson Way, Cambridge CB2 0PY, United Kingdom
b
Erasmus MC, Department of Medical Ethics and Philosophy, Dr. Molewaterplein 50, Office: AE 341, P.O. Box 2040, 3000 CA Rotterdam, Netherlands

A R T I C L E I N F O A B S T R A C T

Article history: Should patients with Parkinson’s disease participate in research involving stem cell treatments? Are
Received 11 September 2012 induced pluripotent stem cells (iPSC) the ethical solution to the moral issues regarding embryonic stem
Received in revised form 4 April 2013 cells? How can we adapt trial designs to best assess small numbers of patients in receipt of invasive
Accepted 12 April 2013
experimental therapies?
Available online 7 May 2013
Over the last 20 years there has been a revolution in our ability to make stem cells from different
sources and use them for therapeutic gain in disorders of the brain. These cells, which are defined by their
Keywords:
capacity to proliferate indefinitely as well as differentiate into selective phenotypic cell types, are viewed
Stem cells
as being especially attractive for studying disease processes and for grafting in patients with chronic
Parkinson’s disease
Neural grafting incurable neurodegenerative disorders of the CNS such as Parkinson’s disease (PD). In this review we
Disease modelling briefly discuss and summarise where our understanding of stem cell biology has taken us relative to the
Clinical trials clinic and patients, before dealing with some of the major ethical issues that work of this nature
Ethical issues generates. This includes issues to do with the source of the cells, their ownership and exploitation along
with questions about patient recruitment, consent and trial design when they translate to the clinic for
therapeutic use.
ß 2013 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
2. The use of stem cells for neurodegenerative diseases; the current clinical status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
3. The use of stem cells for neurodegenerative diseases; ethical issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.1. The cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.1.2. The moral status of the embryo and ES cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.1.3. The potentiality argument and IPS cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.1.4. Foetal material and its relationship to stem cell research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.2. The patient and problems of compromised decision making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.3. The clinical trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

1. Introduction

Abbreviations: hES, human embryonic stem cells; HD, Huntington’s disease; iPS, The clinical application of stem cells, over the past 20 years, has
induced pluripotent stem cells; iN, induced neurons; PD, Parkinson’s disease; VM, moved from the treatment of blood disorders and malignancies to
Ventral mesencephalon. many different areas of medicine including, neurological disease.
* Corresponding author. Tel.: +44 1223 331160; fax: +44 1223 331174.
Stem cells raise the possibility of replacing and restoring cells lost in
E-mail addresses: rab46@cam.ac.uk (R.A. Barker), i.debeaufort@erasmusmc.nl
(I. de Beaufort). disease processes of the central nervous system (CNS), most notably
1
Tel.: +31 010 7044145; fax: +31 010 7044735. for Parkinson’s disease (PD), where trials to replace the lost nigral

0301-0082/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.pneurobio.2013.04.003
64 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
dopaminergic neurons using foetal ventral mesencephalic grafts
have proven efficacious in some cases (Brundin et al., 2010; Galpern
et al., 2012; Barker et al., 2013a). Stem cells have also been used as
catalysts of endogenous repair in clinical trials for other neurological
conditions, such as Multiple sclerosis (e.g. Connick et al., 2012) and
stroke (Nelson et al., 2002; Savitz et al., 2005; Kondziolka et al., 2005,
2000). This review focuses on how stem cells have come to be
considered for use in chronic neurodegenerative conditions,
especially PD. It then considers the ethical issues raised by their
use, especially in light of the growth of stem cell tourism for
neurological conditions (Daley, 2012; Taylor et al., 2010).
A stem cell is defined as a cell that has the ability to
continuously divide and differentiate (develop) into various other
kind(s) of cells/tissues, and as such one can generate, in theory,
large numbers of cells from a limited source. This therefore makes
them attractive to modern medicine in three major ways:
1. They can be grown and differentiated into a relevant cell type for
grafting to replace cells lost in a disease process (e.g. the
dopaminergic nigral neurons in PD).
2. They can be used to study disease if they can be grown and
differentiated from the patient themselves as is now possible
using inducible pluripotent stem (iPS) cells or inducible neuronal
(iN) approaches (reviewed in Robinton and Daley, 2012).
3. They can be grown and differentiated into the relevant cell type
(using either of the above approaches) and then used in vitro for
drug screens to identify agents that may be therapeutically
useful.
Fig. 1. The different types of stem cells that are being considered for use in the study and treatment of neurodegenerative disorders of the CNS and their relevant advantages
and disadvantages.
There are many different sources of stem cells and each brings
with them their own distinct advantages and disadvantages (see
Fig. 1). They can broadly be thought of in terms of whether they are
derived from the embryo (e.g. embryonic stem (ES) cells) or foetus;
or from the adult (e.g. bone marrow mesenchymal stem cells).
Those derived from the developing embryo or foetus tend to have
greater capacity for expansion and differentiation but bring with
them safety issues of tumourigenicity and ethical problems related
to the destruction of the embryos/foetus. In contrast adult derived
stem cells possess less tumourigenic potential as well as being
ethically less controversial, but display problems of limited
proliferative and differentiation potential. This distinction, though,
has been challenged by the development of iPS cells or iN
approaches; technology that involves harvesting adult somatic
cells and reprogramming them to either a pluripotent stage with
all its properties or direct transdifferentiation to neurons
(Takahashi and Yamanaka, 2006; Vierbuchen et al., 2010).
2. The use of stem cells for neurodegenerative diseases; the
current clinical status
The ability to generate stem cells and their progeny for use in
neurodegenerative disorders of the CNS builds on a background of
many years of work looking at primary cell sources for CNS repair.
This work is best exemplified by studies that have used primary foetal
tissue for cell replacement in PD and Huntington’s disease (HD).
In these studies the rationale has been that each disease has a
unique and critical core pathology; namely the loss of the nigral
 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
dopaminergic neurons in PD and the GABAergic striatal output
neurons in HD, and that replacing them with their foetal equivalent
would restore the network back to normal and by so doing repair
the brain and relieve the patient of their symptoms and signs. So far
this has proven to be a useful approach in some patients and has
provided ‘‘proof of principle’’ data which has been helpful in
supporting work aspiring to develop novel stem cell based
treatments for use in this way.
The loss of the nigral dopaminergic neurons in PD was first
recognised over 50 years ago and led to the successful introduction
of dopaminergic drugs to treat this condition in the late 1960s. While
these therapies have proven to be very useful (and by so doing
highlights the fact that simply replacing dopamine alone has a major
clinical benefit), they also generate side effects over time which in
the long term can be problematic (Toulouse and Sullivan, 2008).
These problems include unpredictable motor responses (on–off
phenomena) and drug induced dyskinesias, both of which can be so
disabling that other treatments are needed including continuous
enteral dopamine infusions or deep brain stimulation (Nyholm,
2012; Clarke et al., 2009). These complications, coupled to the fact
that these drugs do not arrest or slow down the disease process, led
during the 1970s to the search for more definitive, reparative
therapies. In the first instance this took the form of cell based
therapies that in the 1980s led to clinical trials with dopamine cell
transplants; initially adrenal medullary chromaffin cells ahead of
the more successful foetal ventral mesencephalic (VM) allografts
(reviewed in Brundin et al., 2010; Galpern et al., 2012). These latter
transplants involve harvesting the developing midbrain from
human foetuses collected from termination of pregnancies (abor-
tions) and then grafting them heterotopically to the striatum of
patients with PD, especially the putamen which is the site of greatest
dopamine loss in this condition (e.g. Lindvall et al., 1990; Widner
et al., 1992; Spencer et al., 1992). This need to place them in the
striatum stemmed from the experimental observations that grafting
such cells to the site of cell loss, namely the nigra was without benefit
(Björklund et al., 1983). Of late successful studies have been
undertaken in which VM grafts are placed both in the striatum and
nigra in PD patients; although it is unclear whether they offer
benefits beyond those seen in patients solely in receipt of striatally
placed nigral grafts (Mendez et al., 2005).
Transplants of VM tissue, while containing the critically
important nigral dopaminergic neurons, also contain many other
cells of the developing VM, which initially were thought to be
necessary for supporting the developing dopaminergic neurons.
This is probably true, but it has subsequently been shown that
some of these transplanted cells have effects in their own rights
such as the role of serotoninergic neurons in the genesis of graft
induced dyskinesias (GIDs) (reviewed in Barker and Kuan, 2010).
Nevertheless the initial open label studies with VM allografts in
patients with PD produced a significant clinical benefit in many
patients with evidence that the transplanted nigral dopaminergic
neurons survived, released dopamine and formed connections to
and from the host brain (Piccini et al., 2000; Piccini, 2002;
Kordower et al., 1995, 1997). This ability of the grafts to exert long
term functional benefits to the patients does not mean that they
are necessarily protected from the ongoing Lewy body disease
process (Kordower et al., 2008; Li et al., 2008), but that such a
process does not critically compromise them in the short term. In
other words, whilst it has now been shown that alpha synuclein
pathology can be found in the graft, this does not negate the motor
benefits that they offer some individuals with PD over many years
(e.g. Politis et al., 2010, 2011; Ma et al., 2010).
Although VM grafts can be very effective in some PD patients, a
number of problems existed with this approach from its very
inception, which have always prevented their widespread
adoption. These problems included:
65
(i) The need to collect the tissue from terminations of pregnancy;
i.e. abortion, and the ethical issues that this creates (see
Section 3.1.4).
(ii) The need to collect VM tissue from multiple foetuses (e.g. 8–
12) in order to have sufficient numbers of nigral dopamine
cells for grafting a single individual which creates major
logistical problems in obtaining sufficient material.
(iii) The fact that every patient has to have their own unique
transplant derived from the donated aborted foetuses
available at the time of grafting, something which may
contribute to the variable results seen in patients grafted using
this approach including the lack of efficacy in some cases and
graft induced dyskinesias (GIDs) in others.
(iv) The advent of more sophisticated therapies (e.g. DBS) for
effectively treating the same problems that the cell therapies
were trying to help, namely the complex dopaminergic
responsive aspects of PD.
(v) Issues to do with the fact that the major determinants of quality
of life in PD are the non-dopaminergic, non-motor features of
the condition. As such any dopamine cell therapy would have
limited impact on disease burden and measures of quality of life
(Chaudhuri and Odin, 2010; Williams-Gray et al., 2009).
As a result there has been a great deal of debate about whether
pursuing a dopaminergic cell based therapeutic approach to PD in
the 21st century is sensible or useful (Olanow et al., 2009; Galpern
et al., 2012), especially in the light of the two negative double blind
placebo controlled trials using foetal VM tissue in patients with PD
(Freed et al., 2001; Olanow et al., 2003; also see Section 3.3).
However, a consortium of researchers, supported by the EU
(TRANSEURO; http://www.transeuro.org.uk/pages/disease.html)
are planning a new foetal VM trial in PD. This is predicated on
the grounds that VM transplantation can have a major effect on
quality of life (e.g. Politis et al., 2010) and that the variable outcomes
to date relate to a number of issues that need to be systematically
addressed and resolved. As such by controlling more carefully for
patient selection and tissue preparation and grafting, more
consistent benefits can be found which will impact significantly
on the natural history of this condition whilst not curing it.
This work will initially involve a new foetal VM transplant trial
which will then serve to lay the foundation for the first round of
trials using stem cell derived dopaminergic neurons.
The source of stem cells to be used in this way is currently
unknown but is most likely to be a human embryonic stem cell
(hES) line. The reason for this is that the ability to generate
authentic nigral dopaminergic neurons from such a source is now
possible, although has still to be optimised (Kriks et al., 2011;
Ganat et al., 2012). In addition some of the previous worries,
concerning teratoma and overgrowth of forebrain neural precursor
cells from ES cell derived cells, seems also to have been solved.
What still remains an issue is the extent to which the dopaminergic
neurons so derived can generate normal fibre outgrowth and
recapitulate the re-innervation potential of the foetal dopaminer-
gic cells in vivo. Whilst this question of fibre outgrowth remains a
scientific challenge, the use of ES derived cells, as with the use of
foetal cells, bring(s) with it significant ethical issues as well. Adult
stem cell sources avoid these issues to some extent, but are
nevertheless much less effective at repairing brains both experi-
mentally and in the few clinical trials that have used them (Lee
et al., 2008, 2012; Quinn et al., 2008) (see also Table 1).
In the related neurodegenerative condition, HD, the efficacy of
human foetal striatal allografts is less well proven (Wijeyekoon
and Barker, 2011). In part this is because the pathogenic process is
a much more distributed process from disease onset (Tabrizi et al.,
2012) and thus the loss of striatal cells is only part of a much
broader pathogenic process. As such, solely targeting this structure
66 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
Table 1
Major published clinical trials of cell based therapies in neurodegenerative disorders of the CNS.
Condition Cell type
Parkinson’s disease
Ventral mesencephalon
Adrenal medulla
Retinal pigment epithelial cells
Other cell types (Carotid body; Superior Cervical Ganglion)
Huntington’s disease
Foetal striatal allografts
Multiple system atrophy (MSA)
Mesenchymal stem cells
Motorneuron disease
Mesenchymal Stem Cells
Other clinical trials involving cell transplants include
Stroke: ‘‘Stem cells’’
Multiple sclerosis; Mesenchymal stem cells;
Spinal cord injury Various different types
will only ameliorate some, and even then not the most disabling,
aspects of the condition. In addition the number of patients in
receipt of such foetal allografts to date is much less than in PD, and
so their efficacy is less well proven both in terms of sustained
clinical benefits and imaging correlates of surviving striatal tissue
(Bachoud-Lévi et al., 2000, 2006; Reuter et al., 2008; Freeman et al.,
2000). Furthermore post-mortem studies on grafted HD patients,
who have died years after receiving their striatal transplants, have
revealed poorly surviving grafts with pathological changes within
them that mirror, to some extent, that which is seen in the host HD
brain (Cicchetti et al., 2009; Soulet and Cicchetti, 2011). Thus the
rationale for developing striatal GABAergic neurons from a stem
cell source for transplantation in patients with HD is less clear cut,
although the ability to make such cells is now possible (Ma et al.,
2012; Carri et al., 2013). Furthermore whatever the scientific issues
related to this approach, the ethical concerns remain the same with
regard to the type of cell being used. In addition, in HD there are
other ethical problems that arise with the patients given the early
cognitive deficits that appear as part of the disease process.
Overall there is evidence that cell replacement strategies can
work in certain neurodegenerative disorders of the CNS, especially
PD and to a lesser extent HD. Other neurodegenerative diseases of
the CNS have also been the subject of cell based therapies including
Multiple System Atrophy (MSA) (Lee et al., 2008) and motorneuron
disease (Mazzini et al., 2003, 2008, 2012) (see Table 1), although
whether such treatments really help in these disorders is
unknown. Nevertheless these studies have all shown that grafting
human tissue to the adult CNS in patients with neurodegenerative
disorders is safe and can be extremely effective in some cases. As
such we have proof of principle experiments to show that foetal
neural grafts can have functional benefits in some patients with
neurodegenerative disorders and so trying to do the same with a
stem cell based approach should, in theory, be as effective,
although brings with it further ethical issues.
3. The use of stem cells for neurodegenerative diseases; ethical
issues
3.1. The cells
3.1.1. Introduction
A major ethical concern with the use of stem cells for treating
patients with neurodegenerative disorders relates to their origin
(see Fig. 1). The International Society for Stem Cell Research (ISSCR)
Response Reference
Mixed Reviewed in Barker et al. (2013a)
Failed Reviewed in Barker and Dunnett (1993)
Failed Gross et al. (2011)
Failed Mı́nguez-Castellanos et al. (2007)
Itakura et al. (1994)
Mixed Reviewed in Wijeyekoon and Barker (2011)
?Useful Lee et al. (2008)
Lee et al. (2012)
?Useful Mazzini et al. (2012)
Boulis et al. (2011)
?Useful Reviewed in Bhasin et al. (2012)
?Useful Connick et al. (2012, and references therein)
?Benefit Reviewed in Harrop et al. (2012)
emphasises this in the introduction to its guidelines. ‘‘Scientific,
cultural, religious, ethical, and legal differences across interna-
tional borders affect how early stages of human development are
viewed, and how research on human embryos and embryonic stem
cells is conducted’’ (International Society for Stem Cell Research.
Guidelines for the Conduct of Human Embryonic Stem Cell
Research, December 2006. www.isscr.org). It has also been the
subject of a large number of publications (e.g. Harris, 2007;
Zarzeczny et al., 2009; Robertson, 2010). This though is not the
only area of ethical debate as there are clearly issues to do with the
patient, the consenting procedure and any trial designed to use
them clinically (Barker and Coles, 2011), all of which we will
discuss.
3.1.2. The moral status of the embryo and ES cells
The key ethical issue with the stem cells most likely to be of
clinical use (i.e. human ES [hES] cells) relates to how they are
derived and what that means for the embryo from which they are
generated; as the generation of a hES line entails the destruction of
the embryo. Thus the essential ethical issue with hES cells relates
to the moral status of the inner cell mass of the blastocyst, namely
at what point does humanness or personhood start in the
developing human embryo or foetus?
In response to this question a number of different positions can
be adopted. One is the gradualist approach, where the embryo
becomes more human and more deserving of protection as it
develops biologically, although with this view there still comes a
point at which a critical threshold is passed. This is the position
adopted in law in many countries. The alternative view states that
there is a clear threshold beyond which the cells become a person
with human rights but that before this, it does not. Historically,
different times have been suggested for the emergence of
personhood or ensoulment: at fertilisation; at the time beyond
which twinning is no longer possible; at the time of quickening
(first foetal movements); at times of viability (i.e. the capacity to
survive outside the womb); or at birth (Jones, 2004; de Wert and
Mummery, 2003). Some would argue, though, that given the
difficulties of establishing a clear and acceptable threshold,
the embryo should be considered to be a human person and so
the destruction and use of the cells to make cell lines should not be
allowed at any stage. However, whatever one’s position in the
debate, to bestow the same dignity and respect to human embryos
from the very beginning as to persons has consequences beyond
the use of ES cells in research and includes contraception and
 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
abortion for example. As such it is debatable whether there will
ever be agreement on this or even an agreement to disagree!
(Espinoza and Peterson, 2012) For this reason, some authors have
accepted that there are irreconcilable differences and sought to try
and move the debate on beyond this point. For example, Hug and
Hermeren have given their book on Translational Stem Cell
Research, the subtitle ‘Issues Beyond the Debate on the Moral
Status of the Human Embryo’ (Hug and Hermeren, 2010).
In a short review such as this, these questions can only be
presented and cannot be fully answered, but for those who wish to
read more about this we recommend de Wert and Mummery
(2003), the ISSCR guidelines (Espinoza and Peterson, 2012; Harris,
2007; Robertson, 2010; Zarzeczny et al., 2009).
3.1.3. The potentiality argument and IPS cells
Attempts to generate human stem cells, whilst avoiding ethical
concerns to do with embryo destruction, have been explored and
include techniques to isolate individual cells from the developing
blastocyst without destroying it (Klimanskaya et al., 2006). Whilst
such an approach was heralded as a great breakthrough in the
ethical use of ES derived cells, the ability to do this without actually
destroying the embryo has proven problematic. Alternatively, iPS
cells have been championed as being an ethically more acceptable
source of stem cells as they have properties similar to ES cells but
can be made from adult human cells e.g. skin fibroblasts
(Takahashi et al., 2006). This approach avoids the ethical issues
intrinsic to human ES work whilst also providing tissue that is
easily available (from the patient directly) and which in theory
could be grafted back into that same patient without risk of
immunological rejection (i.e. autografting) (although see Zhao
et al., 2011). This latter strategy is intuitively more attractive, but
does bring with it concerns that the disease being treated may also
develop in the grafted tissue given it is derived from the patient
themselves. Furthermore the moral status of iPS cells remains
controversial (Zarzeczny et al., 2009; Fung and Kerridge, 2013),
and central to this is whether or not such cells can generate a
human person in much the same way as an ES cell. In other words,
do IPS cells have the potential to become a person in the same way
as a human ES cells? If so then the arguments prohibiting the use of
one should apply to both, if indeed potentiality lies at the basis of
the moral status – the argument being not that the embryo is
already a human person, but that it could become a human person,
and as such deserves protection.
The question that then arises is whether potentiality, even if
granted, is a good ethical argument by which to bestow the same
rights, respect or dignity to the potential entity (embryo) as to the
later entity (human person). This is philosophically and ethically
not self-evident. In addition these arguments have impacted on a
new issue that has arisen of late which relates to the patenting of
any cells so obtained for widespread clinical use. In this case, the
question emerges, that if a useful human stem cell line can be
derived and differentiated into a neuron of widespread clinical use
(e.g. a nigral dopaminergic neuron), should those who have
developed the protocol be able to patent that procedure? The Court
of Justice of the European Union has recently ruled on the
patenting of neural precursor cells produced from human ES cells
and come to the opinion that this is not allowed (Callaway, 2011;
Smith, 2011). The Court in making this decision, emphasised the
importance that the ability to start ‘the process of development of a
human being’ is a quality that some stem cells possess (Court of
Justice of the European Union, Press Release No. 112/11, 18
October 2011 Judgement in Case C-34/10 Oliver Brustle v
Greenpeace e.V.). As such human dignity should be applied to
‘the human body from the first stage in its development, i.e. from
fertilisation’ so that cell lines that are derived from embryos and by
so doing their destruction, should not be patented in the EU. This
67
decision has generated much debate. On a practical level, such a
ruling runs the risk that funding and developing such a therapy will
have no financial payback and as such attract no investment,
including research funding. In addition, if any such ruling is not
made across the globe then those working within the area of the
ruling will be disadvantaged compared to those working in other
parts of the world.
This decision and its practical implications demonstrate, as we
wish to repeatedly emphasise, that stem cell work generates not
only a theoretical philosophical, ethical and legal debate, but also has
important consequences for how researchers are treated and what
research can actually be done. Indeed the ruling runs the risk of
suggesting that those who consider the embryo to have a moral
status similar to a person have the better (or only good) moral point
of view and as such this should dictate the direction of this whole
field of research. This is clearly not useful especially given that it is by
no means certain that adult stem cells nor iPS cells are a good (both
morally and therapeutically speaking) alternative to ES cells.
3.1.4. Foetal material and its relationship to stem cell research
Whilst much of the debate on stem cells and their use in human
neurodegenerative conditions concentrates on ES cells, tissue from
the developing human foetus has also been used for the generation
of stem cells for grafting in such patients (Ribeiro et al., 2012). The
use of foetally derived material is also fraught with moral issues as
briefly touched on above (see Section 2). Such tissue is obtained
from a planned medical and surgical (as oppose to spontaneous)
abortions. Whilst its use is therefore contentious for this reason, it
is important to recognise that abortion is legal in many countries,
and so pragmatically one can argue that there is less of an issue
with using foetal tissue for therapeutic use given it would
otherwise be discarded. This is a common position which is
facilitated by clear guidelines on the responsibilities of the teams
involved with the termination of pregnancy and the team wishing
to use the foetal tissue. In the UK these guidelines are clear and
ensure that the decision to terminate a pregnancy is done
independently of any decision to use that tissue for research or
therapeutic purposes, in other words there is no option to donate
tissue to a specific/designated recipient (Polkinghorne et al., 1989;
Keown, 1993). There are also procedures in place to ensure that
there is adequate separation between the team counselling the
pregnant woman and carrying out the termination of pregnancy
and those using any tissue that is obtained by that process. This is
to make sure that the decision on having an abortion is not
influenced in anyway by those wishing to use such tissue. However
others would argue that simply knowing that the foetal tissue
could be used for research would encourage women to have
abortions. Whilst this is a commonly cited anxiety for using foetal
tissue for medical research, there is no evidence suggesting that
this happens.
3.2. The patient and problems of compromised decision making
One of the major issues that uniquely confront the field of
neurodegenerative disorders is that the patient being considered
for any experimental stem cell therapy has a condition that in some
way may affect their cognitive capacities and abilities to make
rational decisions. Often these deficits are subtle, especially in
early disease, but can become more of an issue with disease
progression and some of the drug treatments used to treat it. For
example, in PD many patients dement during the disease course
(e.g. Williams-Gray et al., 2009). Furthermore there is evidence
that dopamine agonist drugs can induce pathological gambling
and risk taking behaviours, especially in men with younger onset
disease which could impact on their ability to make any measured
decision on joining a new experimental stem cell transplant trial
68 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
(Singh et al., 2007; Weintraub et al., 2010; Voon et al., 2007;
Djamshidian et al., 2012).
So who should be included/participate in any new stem cell
based trials? In the case of a novel stem cell based treatment for
patients with neurodegenerative disorders, given that safety rather
than efficacy is the major issue in the first into man trials, this issue of
altered risk perception may not be an immediate problem. In this
situation the recruited patients tend to have more advanced disease
and have failed standard therapies. Given that they have the ‘‘least to
lose’’, this seems intuitively fair, although different patients may
perceive this in very different ways. However, the selection of such
patients with advanced disease, does run the risk that it may actually
compromise the trial. This is because whilst safety is the primary
issue, some signal of efficacy is needed which may be difficult, if not
impossible, to measure in such patients given that they lie at a point
in their disease when the brain cannot realistically be repaired. For
example, if the stem cell therapy works in part in PD by causing the
host dopaminergic system to regenerate then this may not be
possible in advanced patients as the system has already totally
degenerated. These patients with an advanced state of the disease
may also be particularly susceptible to the problems of ‘therapeutic
misconception’ in which they believe that the trial will be in their
direct interests and improve their condition, while in fact this is
unlikely and/or improbable. The informed consent process must
make this clear to the patient. Therefore it may be ethically more
acceptable on a broader level to target the population who are
ultimately most likely to benefit from the therapy even though they
have ‘‘more to lose’’ if it were to go wrong. This in turn brings us back
to the problems of choosing patients in the early stages of disease
and the difficult ethical dilemma this presents in terms of altered risk
perception and cognition.
This issue of risk and risk perception is a difficult one as this
varies between individuals and in the case of PD may be altered,
without being recognised, by drugs that the patient takes for their
condition (Politis et al., 2010; Ho et al., 2006). In other words,
should such a patient, on a drug that can cause this (e.g. dopamine
agonists), be offered a new experimental therapy when they may
not be able to truly understand the risk they are signing up for with
the new therapy? In the case of PD should their dopamine agonist
therapy be stopped and/or substituted with L-dopa therapy (and
the risks that this brings with it in terms of long term motor
complications) and their capacity to fully understand risk re-
examined? Indeed in many cases there is often no objective
evidence for any major change in their behaviour. However, given
that these drugs could do this, coupled to the reluctance of the
patient to confess to these abnormal behaviours, physicians may
conclude that no patients on such treatment should be offered
experimental therapies with stem cells even in the absence of
objective evidence of a dopamine dysregulation syndrome!
In addition to these issues of risk perception are also concerns
about the cognitive changes that the disease creates and which is
altered by disease progression and treatment. For any individual
patient being considered for recruitment to a trial, the acceptable
risks of an experimental treatment are balanced against the
perceived disabilities and prognosis of that disease. The physician
therefore not only has to explain the trial procedures and risks, but
also needs to ensure that the patient has a reasonable understand-
ing of their disease and prognosis, and that the family and carers do
as well. As already stated this can be altered by medication but also
through the disease itself. So for example, in PD cognitive deficits
including dementia are common in advancing disease (Williams-
Gray et al., 2009) and will obviously interfere with the ability of
that patient to fully appreciate the treatment and trial aims.
However, even in early disease, dysexecutive problems are seen
(Foltynie et al., 2004; Williams-Gray et al., 2009), which in theory
can also adversely affect the ability to assimilate complex and
competing sets of information as would be needed to consent to
any stem cell therapy trial. This is even more of an issue when there
are greater cognitive deficits, especially of a dysexecutive nature,
from disease onset as occurs in HD. In this condition, cognitive
deficits are an early (if not the earliest) feature (Ho et al., 2003) of
the disease and so all patients being recruited to the trial will have
lost some of their cognitive capacities, which in the more advanced
stages of the disease equates to a frank dementia. Thus advanced
HD patients cannot be considered for experimental trials of this
nature, not only because the therapy may be ineffective in the face
of such advanced widespread pathological changes which in itself
is a good enough reason of course (see above) but also because the
patient has very limited capacity to understand what is being
asked of them in terms of the experimental nature and risks of
taking part in the trial.
So as part of the consenting procedure, each potential trial
participant has to receive an explanation of the pros and cons of
the trial from a qualified individual in language and detail tailored
for their particular situation and background. This is usually best
done at several meetings and indeed should be a continuous
process, although even then this does not necessarily lead to truly
informed consent. So, for example, in an audit of patients in an MS
trial using a new monoclonal antibody conducted at one of our
centres, a high level of satisfaction with the consenting process
was reported. However, there was a surprising inability of
participants to remember the aim of the trial and the chief
adverse effects of the investigational drug (Cox, 1999), despite the
pros and cons being explained to the patient on several occasions.
This trial involved young patients with early stage MS with no
obvious cognitive deficits, so how will older patients with disease
that affects their cognitive capacity fare in such a process? This
therefore raises a question as to whether any patient should be
expected to pass a test on these issues before being allowed to take
part in the trial, or whether one accepts that patients often only
take in some of the information and that is all one can realistically
expect?
In addition to all this, being involved in experimental
therapeutic trials brings with it a major commitment from the
patient and family/carer. This involves not only a high intensity of
visits and assessments but also the possible publicity that may
ensue or be wrapped up with the study from its inception. Some
patients may not feel they are physically or mentally up for this
and so recruitment may be influenced by issues to do with patient
support and robustness. This could also work in the other direction,
such that certain ‘‘self-publicising’’ types of patients may be keen
to be involved in trials which could then run the risk that they may
seek to publicise their experiences ahead of the trial end point and
by so doing could compromise any blinded outcome measures.
Asking patients not to do this is an obvious requirement, but it is
not possible to enforce it.
Wrapped up in this whole consenting process is the further
issue of the attitude of the patient and physician to uncertainty and
the fact that the physician has to occupy a position of therapeutic
clinical equipoise, whilst nevertheless recruiting the patient to an
experimental treatment (discussed also in Galpern et al., 2012). It
is, of course, hard for the physician to remain totally neutral about
any new experimental treatment, and yet still offer it to a patient
even as part of a trial. The clinician must have some belief that the
treatment could help, otherwise he would not be able to enter
patients with their best interests at heart, and as such clinicians
always have some bias in trials of this nature. Critically though the
clinician has to remain neutral as to whether the new treatment is
actually better than the other treatments that are available, as
studies frequently show that the hope about a new treatment are
not justified when proper trials are conducted. This can be
minimised by using double blind placebo trial structures (which
 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
bring with them their own major issues; see Section 3.3) or blinded
third party raters in open label studies.
Finally, even in cognitively intact patients, rational thinking
may be distorted by the hope, even desperation, that the treatment
might give personal benefit; which is not unreasonable for early
trials of a new treatment, especially given that all neurodegenera-
tive conditions of the CNS are currently incurable. This, in turn, can
be made worse through poorly researched media reports or
internet sites offering unproven stem cell therapies at special
clinics (Chen and Gottweis, 2011). Indeed, Zarzeczny et al. in their
recent article on iPS cells emphasise the need for a thorough ethical
examination considering ‘‘the impact of the increasing pressure to
move towards clinical translation and commercialization’’ (Zar-
zeczny et al., 2009).
Such hope cannot be completely taken away from the patient
but does need to be factored into the process, as while it is one
thing to respect the hope people have, it is something else to
crudely exploit it. In this respect, the patient and family may have
very different attitudes and understanding of the procedure and
this in itself can set up a tension as to who is driving the decision
making process with concerns about pressure and coercion. This is
becoming more of an issue with the development of clinics around
the globe offering stem cell therapies for any number of
neurological conditions (Chen and Gottweis, 2011). In such
circumstances, desperate patients and families will often travel
for unproven therapies on the grounds that such treatments claim
benefit, and offer some hope (however small). This is especially the
case when the patient is either unable to make any decision (e.g. a
child with cerebral palsy; an adult with an advanced neurodegen-
erative condition) or because such therapies are not legally
allowed in their country of residence.
This latter issue is becoming an increasing problem as stem cell
tourism gains prominence through the web and with it access to
unproven therapies that prey on vulnerable and desperate patients
and families. This is very worrisome and one would hope that
despite the difficult situation in which many patients find
themselves, they do not lose the capacity to critically analyse
such offers. In this respect the ISSCR patient handbook was written
for such a purpose and provides useful help on assessing the
relative merit of any stem cell therapy being offered for therapeutic
use in patients (www.isscr.org/clinical_trans/pdfs/ISSCRPa-
tientHandbook.pdf).
In fact, this whole area of stem cell tourism has created a
significant number of other problems and these include:
1. Confusion about what is meant by stem cell therapies and what
they can realistically be expected to do therapeutically. Thus the
public, patients and physicians can get confused as to the
different types of stem cells that are advertised for therapeutic
use as they do not realise that there may be very different
scientific rationales and financial motives underpinning their
clinical use. This also includes unrealistic expectations as to the
true long term benefits of these therapies, given that patients
attending some clinics only have follow up over days and weeks.
These reports with limited follow up further distort what is
claimed, which infects the whole field with an over developed
sense of optimism.
2. The risk of severe side-effects and even death with such
treatments (Amariglio et al., 2009) could adversely affect the
development of all stem cell therapies across the world
including centres conducting scientifically rational trials.
3. A pressure to rush a well researched experimental stem cell
therapy to clinical trials in order to stop this type of work being
developed in less rigorously regulated clinics.
4. Confusion as to why stem cell trials are not being done in more
clinics in Europe and the US, as issues of ethics and cost can often
69
be cited by clinics charging for such treatments as the sole
reasons for them not being done in the west.
Finally the role of the private sector in the adoption and
development of stem cell therapies has to be considered at some
point in the delivery of any such therapy to patients. The reality is
that few academic individuals or institutions have the resources or
abilities to take an experimental therapy to the clinic as a major
new therapy. Such a transition requires input from commercial
sources and with this come issues of transparency; investor
confidence; shareholder dividend etc. Whilst in the early stages the
work can be driven by scientific questions, with time the need to
take the treatment out to a broader group of patients will bring
with it financial issues of recompense and development. At such
times, the way the work is done and presented may change.
3.3. The clinical trial
The need to design a trial to test a new stem cell therapy is not
straightforward with respect to safety versus efficacy as we have
discussed already. In fact whilst often not considered as such, trial
design is an ethical issue. In any clinical trial there has to be a
balance between what can be achieved in an individual participant
versus the potential gains to the wider group of individuals with
that disorder. For those trial patients receiving the therapy, the
possible good should outweigh the potential harmful effects of that
treatment; even in the context of a position of therapeutic
equipoise. In some cases patients may feel that even if the benefits
and risks are not vastly different, it is still worth pursuing as they
take a more altruistic view of such trials. For example patients with
HD will often agree to be involved in trials because they feel that
while it may not benefit them directly, it may help the next
generation including their children. In addition a well-conducted
trial, irrespective of its result, should advance understanding of the
disease and so benefit a wider population than those just involved
in the study. A definite negative trial result minimises the potential
harm to the wider community, whereas an inconclusive trial is a
waste of resources, time and participants’ good will.
Underpowered trials fall into this category and have been the
source of much discussion in trials of foetal VM tissue in PD. On the
background of a number of successful open label studies using this
approach (reviewed in Brundin et al., 2010; Barker et al., 2013a;
Galpern et al., 2012), the NIH in the USA supported two double
blind placebo controlled trials, with 20 and 23 patients being
grafted in the two trials respectively with control arms (sham
surgery) of 20 and 11 respectively (Freed et al., 2001; Olanow et al.,
2003). This size of cohort is clearly small and many have argued, as
they did in a similar size GDNF study in PD, that they are not
powered to show efficacy and in fact are not even powered to show
safety (Lang et al., 2006; Galpern et al., 2012). This is important
because the result of these two trials, both of which failed to meet
their primary end point, has been to bring to an end all foetal VM
trials in PD on the grounds that two definitive studies have shown
that such an approach is ineffective. Such a conclusion is
premature not only because of issues to do with the size of the
trial, and thus its power, but also because longer term follow up of
patients in one of these studies has shown efficacy (Ma et al., 2010).
Furthermore both trials had significant methodological differences
in them compared to the previous, more successful, open label
studies (discussed in Barker et al., 2013a).
This issue of power and thus the numbers recruited to trials of
this nature is problematic as it is not ethically acceptable to recruit
large numbers of patients to studies trialling invasive treatments,
at least in the early stages of its development. So one way of trying
to improve the power of the study, whilst minimising the risk, is to
randomise patients to immediate or delayed grafting. This allows
for a comparison between grafted and non-grafted patients during
70 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
the first half of the trial and before and after grafting in the delayed
group, with the patients in this arm acting as their own controls.
This approach has been adopted in a large transplant study in HD
(A. Bachoud-Levi, personal communication) as well as being a
feature of the original NIH study by Freed et al. (2001). Of course
this only increases the numbers of patients to a small degree and
suffers from the problem that the control arm disappears with time
as they get treated.
A second issue relating to the use of double blind placebo
control trials involves the sham surgery arm. In medical practice
the proof that a therapy truly works is through a double blind
placebo controlled study where neither the patient nor practition-
er knows whether they are receiving, or been given, the active
agent. Only at the end of the study when the blind is broken can the
efficacy of the treatment be assessed. This is a relatively
straightforward approach in the case of drug therapies (although
even there it can be an issue) but becomes more of a problem with
invasive neurosurgical therapies that involve the injection and
implantation of cells. These issues include:
1. The fact that the control patients should in theory receive an
intracerebral injection of control stem cells, such as dead cells
for example. Most people would deem this as unethical given
the risks of placing needles into the brain to inject substances
known to be ineffective. As a compromise in studies that have
used a sham arm, the control group have received imitation
surgery where a small non-penetrant burr hole is made in the
skull without the dura or brain parenchyma being breached
(Freed et al., 2001; Olanow et al., 2003; Nutt et al., 2003; Marks
et al., 2010). However, is this a sufficient control? Is this a good
use of resources given that patients and medical staff will spend
hours/days in theatre/hospital pretending that a procedure has
been undertaken at the expense of patients with other genuine
neurosurgical problems requiring treatment?
2. The primary end point with biological agents such as cell
implants will probably need to be 3, 5 or more years post-
grafting not the usual 6 months to 2 years given that the implant
will have to survive, mature and integrate. As such any double
blind placebo controlled trial would need to continue with the
treatment blind over such a time period. Such a desire comes
with financial costs and the problems of follow up attrition. Is it
right to prevent sham treated patients from joining other
experimental trials that may be on offer, just so the blinded
follow up can be maintained?
3. The use of adjuvant immunotherapy in cell based trials is not
without risk, and should patients not in receipt of any potentially
immunogenic cells be exposed to such drugs? Obviously one
could give sham drugs instead of such potentially toxic agents, but
this then removes the possibility that these drugs may in some
way have an effect on disease progression. This is theoretically
possible given the fact that diseases of this nature have an
inflammatory element to them (Barker and Cicchetti, 2012).
4. The use of a double blind placebo controlled trial should ideally
only be undertaken once the optimal way to deliver that agent
has been ascertained. In the case of intracerebral injections of
cells, the optimal way to do this is not known, and thus to get to
such a position, a slow iterative process is needed involving
small numbers of patients in open label studies. As such it may
take years to get to the point where one feels confident on how
to definitely deliver that therapy, and trials conducted before
such a time may fail for purely methodological reasons (see e.g.
GDNF trials; Barker, 2006, 2009).
5. Given that in some conditions there are very effective therapies,
is there a need for a control sham surgical arm at all? Thus in the
case of PD, it could be argued that any stem cell based therapy
would need to produce a 50% improvement in the patients
motor abilities to be competitive and effective as smaller
improvements (which are what can be seen with placebo
effects) would suggest that the therapy has no competitive
advantage over currently available treatments (e.g. DBS) and as
such is not worth pursuing further.
As a result whilst there is often no disagreement as to the
ultimate trial design, there is as to when such a trial should be
undertaken and whether the control arm should involve sham
surgery or some other active treatment. En route to this, there is
often confusion as to what can realistically be learnt from long
term open label studies and small double blind placebo control
trials with shorter follow up times; with the former often being
much more informative than the latter. One obvious solution to try
and guarantee getting the most useful data out of these small high
intensity invasive studies would be to:
 Try and establish a central register of all such trials with long
term follow up of all cases. This has perhaps best been illustrated
in PD comparing the long term efficacy (or not) of adrenal
medullary transplants (Gross et al., 1991) to foetal VM allografts
(Barker et al., 2013a). And/or
 Select patients for grafting from a larger matched group of
patients so that the effect of the intervention can be compared
against the natural history data of the matched cohort of
patients. This was done, for example, in the UK HD striatal
transplant study (e.g. Barker et al., 2013b).
Finally once a transplantation trial has concluded, media
attention can be expected. Results may be widely and uncritically
cited, and may well be given more prominence than is justified by
their true clinical impact. This is particularly damaging when
negative trial results are used to judge the whole history and
strategy of neural grafting. A transplant may fail to help a disease,
not because there is anything wrong with the cell therapy itself,
but because the wrong patients have been included, or the trial
design was inappropriate. As such some understanding of how the
popular press will portray any trial findings must be understood
and critically evaluated.
4. Conclusion
In this review we have summarised a number of scientific and
ethical issues in the use of stem cells for neurodegenerative
disorders of the CNS, especially PD. In particular we have sought to
discuss the many facets of this debate and how the clinical
adoption of these cells extends beyond issues of what can be done
experimentally to issues of what is legally allowed in some
countries and union of states. In this respect the political and social
aspects of stem cell work is often driven by ethical issues, which in
many cases concentrates solely on the origin of the cells, especially
with respect to ES and foetally derived cells. However the ethical
debate goes well beyond this and involves questions to do with
patient recruitment and consent as well as trial design. Finally
many scientists and clinicians may feel reviews of this nature are
not relevant to what they do, but ultimately everyone contributes
to the debate as issues to do with the use of stem cells for
neurodegenerative disorders of the CNS are as much governed by
what society will allow and governments legislate for, as to what
the scientists can do in their laboratory.
Acknowledgements
Some of the work in this review has been supported by funding
from the MRC (UK), EU FP7 TRANSEURO and NeuroStemCell grants,
 R.A. Barker, I. de Beaufort / Progress in Neurobiology 110 (2013) 63–73
Cure PD, Parkinson’s UK and the NIHR Biomedical Research Centre
to Addenbrooke’s Hospital/University of Cambridge.
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