1° What is an embryonic
2° How are embryonic stem cells obtained?
3° What are the applications for embryonic
4° What are the problems linked to
the use of embryonic stem cells?
5° Do adult stem cells exist
6° What is therapeutic cloning?
7° What are the European regulations
regarding stem cells?
is an embryonic stem cell?
The human body is made up of several billion
cells. Every one of these cells is derived from a single
'egg cell' produced when an egg is fertilised by a sperm.
But this does not mean that all our cells are identical.
On the contrary, we possess approximately 200 types of cells,
with different features and different functions: neurons
(cells of the central and peripheral nervous systems), liver
cells, skin cells... These specialised cells are said to
Once fertilised, the egg undergoes a series
of divisions, yielding two, then four, then eight identical
cells. These cells are totipotent, meaning that each
one, if isolated and allowed to develop, can form a new
embryo. This is how identical twins result from a single
After the eight-cell
stage (two or three days after fertilisation), the cells
continue to divide, but lose the ability to form a new embryo.
The embryo takes the form of a hollow sphere, known as a
blastocyst, containing an inner cell mass. The outer cells
of the sphere, together with maternal cells, will form the
placenta. The inner cell mass will produce all the tissues
of the child. These are the embryonic stem cells (see
the diagram) (ESCs). They have two remarkable properties:
- they are immortal: if isolated and placed in
a culture medium, they can divide indefinitely, unlike
adult cells which stop dividing after a certain time.
All the descendants of an ESC constitute an embryonic
stem cell line;
- they are pluripotent: in culture under the influence
of appropriate biological and biochemical factors, they
can differentiate into any specialised cell type. They
can reconstitute the cells of any organ except the placenta:
brain, liver, skin, etc.
View the various
types of stem cells (see
2° How are
embryonic stem cells obtained?
In 1998, James Thomson's laboratory at
the University of Wisconsin in Madison (US) (http://www.wicell.org/)
was the first to obtain embryonic stem cell lines from human
embryos at the blastocyst stage, which were produced by
in vitro fertilisation (IVF).
IVF enables some infertile couples to
have children. At each IVF, multiple embryos are collected,
a few of which are reintroduced into the woman's uterus,
the others being frozen and stored in case of initial failure.
They are stored for several years, even if the couple no
longer intends to use them - they may have succeeded in
having a child, decided not to have a child, or separated.
These supernumerary embryos (also
called spare embryos) obtained by IVF are what James
Thomson and his team used to produce the first human ESC
lines. Since then, at least three other laboratories (one
in the US, one in Australia, and one in Israel) have done
In 1998, John
Gearhart's laboratory at the John Hopkins Hospital in Baltimore
(US) used a different method to obtain another line of human
stem cells. The line was obtained, with the parents' consent,
from a foetus aborted at five to nine weeks for therapeutic
reasons. The line was isolated from a cell population destined
to produce the gonads (testes or ovaries). These so-called
primitive germinal cells (PGCs - see
the diagram showing the production of PGCs) seem to
have the same properties as ESCs.
are the applications for embryonic stem cells?
Biologists value ESCs as an important
tool for basic research aimed at elucidating the mechanisms
of development and cell differentiation. However, there
is another reason for the current interest in ESCs: the
prospect of using them for regenerative medicine,
i.e., exploiting their immortality and pluripotence to reconstitute
organs damaged by disease or accident.
Many human ailments are due to cell degeneration
in tissues that doctors are unable to repair. In some cases
an organ transplant may be the solution, but in most EU
countries there is a shortage of donors. Another solution
could be to repair damaged organs with ESCs. The use of
cells as therapeutic tools is called cell therapy, as opposed
to gene therapy, which uses genes.
Regenerative medicine is still in its
infancy. Researchers believe it may take many years to find
the right 'chemical cocktail' capable of inducing an ESC
able to differentiate into the cell type required. In the
medium term, the main applications envisaged for ESC-based
regenerative medicine are:
- First, a group of diseases for which transplantation
is not an option: the so-called neurodegenerative diseases
caused by the death of neurons in precise regions of the
brain: Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis... Several European laboratories have
already developed foetal neuron grafts - which are not
stem cells as they have already differentiated - for the
treatment of Parkinson's disease. For more on this, see
the following websites: http://ec.europa.eu/research/rtdinfo/en/28/dossier2.html
- Some heart conditions might be treated with grafts of
ESC differentiated into cardiac muscle cells. The grafts
would serve to reconstitute the heart muscle and restore
good blood pumping action.
- Another focus is type-1 diabetes, which represents approximately
10% of all diabetes cases. This disease affects young
people and leads to the progressive destruction of the
pancreas. It is now possible to slow its progression by
transplanting islets of Langerhans, cells specialised
in the synthesis of pancreatic insulin, but there are
far too few cell donors to meet the demand. Here, too,
stem cells might solve the problem of organ donor shortage.
- By implanting stem cells differentiated into liver cells,
it might be possible to repopulate a liver destroyed by
a hepatitis virus or by agents that have caused cirrhosis.
- In the longer term, it might even be possible to reconstruct
whole organs of certain types in vitro, and then
transplant them into patients. As yet, only the skin,
cornea, bladder, blood vessels and bones have been considered
for such tissue engineering.
are the problems linked to the use of embryonic stem cells?
In the present state of scientific knowledge,
ESCs appear promising for therapeutic applications because
they readily divide in culture. Yet care must be taken to
ensure that their capacity to divide does not become excessive
and lead to tumour formation. Indeed, non-differentiated
ESCs transplanted at a certain density can lead to the development
of teratomas (embryonic tumours). There is a double risk
of tumour development: ESCs are themselves tumorigenic when
they are not differentiated; and in mice, the culture cell
lines may cause problems of DNA methylation (http://www3.sympatico.ca/diane.demers/methadn/page2.htm).
Methylation is the attachment of a chemical structure called
a methyl moiety (-CH3), in place of a hydrogen atom, onto
one of the DNA bases. This leads to a change in the structure
of the DNA and its interactions with proteins, and abnormalities
of the karyotype (the chromosomes of the cell). These changes
may themselves increase risk of subsequent malignant transformation,
that is, the development of a cancer.
Although ESCs are genuinely pluripotent,
it is not currently possible to direct them all to form
a single type of cell, for example skin cells. As a result,
before ESCs can be used for therapeutic purposes, all the
tumorigenic cells must be eliminated, and the different
cells sorted so that only cells that have differentiated
as required for the therapeutic effect are retained. Further
study is also needed to avoid rejection of the transplant
of ESC-derived differentiated cells by the patient's immune
There are currently tens of thousands
of stored embryos (the exact figure is unknown) in European
IVF centres. They constitute a major reservoir of biological
material for producing ESC lines. Yet some scientists are
worried about depletion of this supply. They believe that
progress in IVF technology will increase the success rate
of embryo implantation, which currently does not exceed
30%. Eventually, they say, it may no longer be necessary
to produce several embryos in order to implant just one.
These scientists believe that in the medium term, spare
embryos will become rare and cease to be available for producing
stem cell lines. A solution might be to generate spare embryos
independently of any parental plan, i.e., solely for research
The use of spare embryos as a source of
'raw material' (in this case, stem cells) also raises an
ethical issue. Some people condemn this reification
of the human embryo (treating it like a 'thing'). Others,
on the contrary, feel that the very fact that these embryos
exist and are stored independently of any parental plan,
and the high hopes they raise for treating certain diseases,
makes their use ethically acceptable. This is the position
adopted notably by the Comité Consultatif National
d'Ethique pour les Sciences de la Vie et la Santé
(National Consultative Ethics Committee for Health and Life
Sciences) in its opinions of 1997 and 2001 (see http://www.ccne-ethique.org/english/start.htm).
PGCs (primitive germinal cells, see
question n° 2) seem to divide less readily than
ESCs, although the available scientific data are scant.
These cells also present an unresolved scientific problem:
are they genetically viable? They are taken from foetuses
that have been obtained from therapeutic abortions. Some
scientists point out that the reason for the abortion may
have been a serious malformation or disease caused by a
genetic defect, which cell lines isolated from the aborted
foetus would be likely to carry. The PGC approach is also
criticised by opponents of abortion.
5° Do adult
stem cells exist?
As the embryo develops, the differentiation
potential of its cells gradually diminishes. In an adult,
some cells can produce only one cell type. Others can yield
all the cell types of a given organ. The latter are called
adult stem cells (ASCs). They are immortal like ESCs, but
they are not pluripotent, since their scope for differentiation
is limited to a few cell types. The haematopoietic stem
cells of the bone marrow, for instance, can only yield blood
cells (red cells, various kinds of white cells, and platelets).
Such stem cells are described as multipotent. ASCs are also
present in certain regions of the brain, in the skin, in
fatty tissue, etc.
However, one of the most surprising discoveries
of recent years is that under experimental conditions ASCs
can also produce cell types other than those they produce
in vivo. In 2000, the team headed by Jonas Frisen at the
Karolinska Institute in Stockholm (Sweden) (http://info.ki.se/index_en.html
) showed that neuronal stem cells from the brain of an adult
mouse can differentiate into kidney, liver, and intestinal
cells (this is called transdifferentiation). Other
scientists have also shown that haematopoietic stem cells
have the potential to regenerate liver or muscle, but with
low efficiency. Other bone marrow cells may be able to regenerate
the heart, and skin stem cells could be transformed into
The ultimate goal of ASC-based regenerative
medicine would be to take stem cells from a patient's bone
marrow, let them proliferate and differentiate into a desired
cell type in vitro, and then reintroduce them into the same
patient to reconstitute an organ damaged by disease or accident.
With such an autograft, there would be no risk of rejection
by the immune system as the patient would be receiving a
transplant of his own cells.
In addition, the use of ASCs does not
raise any of the ethical issues linked to the status of
the human embryo. This is why opponents of abortion and
of the therapeutic use of ESCs recommend this line of research.
Nevertheless, there are technical obstacles
to the use of ASCs. The most problematic is that the ASCs
that have been described are only present in small numbers.
They may also be hard or even impossible to culture in
vitro, as is the case with haematopoietic stems cells.
In contrast, skin stem cells, recently shown to have the
capacity to be transformed into nerve cells, have the advantage
of being easy to culture for long periods.
is therapeutic cloning?
Some scientists believe that one of the
most promising approaches in regenerative medicine is somatic
cell nuclear transfer (SCNT). This technique involves forming
a new embryo by injecting the nucleus of an adult cell into
an unfertilised egg deprived of its nucleus. The cell will
then develop like a fertilised egg, and the resulting embryo
can be used to produce stem cell lines.
SCNT is thus a
cloning technique, since it enables a new embryo to be created
from the genetic material of a single adult cell. Yet unlike
reproductive cloning which aims to give birth to a new being
- a practice formally prohibited in all EU countries - SCNT
aims simply to produce stem cells for cell therapy. This
is why SCNT is sometimes called "therapeutic cloning"
(see the diagram).
SCNT thus combines in a single method
the benefits of ESCs (easy division and wide scope for differentiation)
with those of ASCs (immunological compatibility between
the patient's immune system and the grafted cells).
These advantages explain why the UK Parliament
voted in November 2000 to authorise somatic cell nuclear
transfer for stem cell production. This decision, unique
in Europe, followed a report to the Minister of Health (http://www.doh.gov.uk/cegc/)
stating that SCNT has "great potential for relieving
suffering and treating diseases". The report also
recommended that the transfer of embryos produced by SCNT
to a uterus should be considered a crime.
The European Group on Ethics (EGE) stated
in its opinion of 15 November 2000 (http://ec.europa.eu/european_group_ethics/gee1_en.htm)
that "at present, the creation of embryos by somatic
cell nuclear transfer for research on stem cell therapy
would be premature, since there is a wide field of research
to be carried out with alternative sources of human stem
cells". This position is justified by the fact
that, although there is a difference of purpose between
reproductive cloning and therapeutic cloning, there is no
difference in nature. There is thus a risk that SCNT might
open the way to reproductive cloning.
Another argument is that SCNT requires
a woman to donate an unfertilised oocyte (egg), a major
intervention requiring hormonal stimulation and general
anaesthesia. The EGE stresses the necessity "to
ensure that the demand for spare embryos and oocyte donation
does not increase the burden on women".
Lastly, some scientists fear that SCNT
might lead to the formation of stem cell lines with altered
genes. Such genetic alterations could be undetectable in
the adult, but produce harmful effects, especially carcinogenesis,
after the many divisions that stem cells are likely to undergo.
are the European regulations regarding stem cells?
Europe's ethical and legal pluralism means
that it is up to each Member State to legislate on the status
of the human embryo and on the use of stem cells.
There is no legislation on embryo research
in Italy or Greece.
Research on the human embryo is banned
in Germany, Austria, and Ireland. These countries also prohibit
the production of spare embryos. In France and Belgium,
research on the embryo remains prohibited, but draft bills
authorising research aimed at producing ESCs are being studied.
In Spain, Sweden, Denmark, and the UK,
research on human embryos less than 14 days old is authorised.
Only Denmark and the UK allow the creation of embryos for
research purposes. In the latter country, since 1990 this
research has been limited to work aimed at improving the
efficiency of IVF. Following a report by the Nuffield
Council on Bioethics at the end of 2000, the British
Government extended this authorisation to include cases
where "this research offers substantial hope for
the treatment of serious human diseases". Research
on ESCs does offer such hope.