Given their many facets
- in terms of origin, properties and therefore potential new treatments
- stem cells require European research to operate on many fronts.
Yet amidst this diversity, researchers are focusing in particular
on two fundamental mechanisms: those which control their multiplication,
and those which govern their differentiation.
Several stem cells types
are currently the subject of European projects. Blood precursors
(haematopoietic cells) seem particularly promising. They are found
in bone marrow, where they renew red blood cells, white blood cells
and platelets, and have long been recognised for their benefits
in treatment, as illustrated by the dramatic increase in bone marrow
transplants (currently about 10000 a year). These transplants, which
can treat various genetic diseases and cure patients who have been
subjected to intensive therapies, for example, in treatment for
leukaemia, pose a number of problems which current stem cell research
could help reduce.
Combating transplant rejection
The main problem here is the immune system's rejection
of the transplanted tissues, or Graft versus Host Disease (GvHD),
which is a potentially fatal reaction. To overcome such problems,
doctors seek donors compatible with the patients (such as family
members), but nevertheless there are still many failures. Bone marrow
transplants also have other drawbacks: the donor has to undergo
a general anaesthetic and, most importantly, the patient receives
a heavy immunosuppressor treatment, which often gives rise to other
One solution would be to take the stem cells from the patient himself,
multiply them in vitro, and then reinject them into his body.
Although there has been some success, researchers have not yet succeeded
in multiplying these cells on a sufficiently large scale. However,
an alternative approach with obvious potential is now emerging:
the transfer of blood from the umbilical cord and placenta of newborn
'The umbilical cord blood has major advantages,'
explains Eliane Gluckmann of the Hôpital St Louis in Paris,
coordinator of the Eurocord project. 'The stem cells it contains
have a greater division capacity than those obtained from bone marrow.
Their immune reactivity is also weaker, with the result that they
cause far fewer rejection reactions. Finally, as they come from
tissues destined to be destroyed anyway, their use poses no ethical
problems, providing the parents agree.'
Umbilical cord blood banks have already been set up and are linked
to several continents. They contain more than 85000 frozen transplants,
all ready to be administered to patients who may need them, in line
with their immune profile. The fact that they were obtained from
a foetus means that it is 30 to 40 times easier to find an umbilical
cord blood sample which is compatible with a patient than a bone
A particularly spectacular use of umbilical cord
blood is being studied by the Enfet (European Network for Fetal
Transplant) project, which is devoted to the possibility of treating
foetuses in utero through stem cell transplants (see box entitled
Delivering bubble babies). Other European researchers
are trying to explore a particularly original avenue for combating
GvHD, in which a gene is introduced into the transplanted cells
which causes their 'suicide' in the presence of a given molecule.
In the event of rejection, this molecule could also be used to control
the number of white corpuscles present in the patient.
Finally, as it is relatively easy to isolate haematopoietic
stem cells and then to inject them into a patient, the question
of their possible use in gene therapy has naturally been raised.
One could imagine, for example, a gene being identified which could
provide resistance to the AIDS virus - this is not inconceivable
as it seems that certain individuals are resistant to the virus.
Patients could then be injected with haematopoietic stem cells incorporating
this gene, and would thus be able to retain their immunity. Researchers
are also looking at viruses and protocols which would make it possible
to introduce these genes into cells.
After blood, it is no doubt the nervous system
looks most likely in the short term to draw full benefit from treatments
involving stem cells. Neurons are incapable of division. They are
subject to many pathologies and forms of deterioration which are
threatening to affect an increasing section of Europe's ageing population.
The most studied and best understood of these diseases is probably
Parkinson's disease (a million sufferers in the EU alone), caused
by the deterioration of a particular kind of nerve cell, the so-called
dopaminergic neurons, named after the chemical messenger they produce
A Swedish team has treated patients suffering
from this essentially incurable disease, transplanting nerve tissue
from aborted foetuses (which are very rich in stem cells). Despite
some failures, notable progress has been observed in patients and
further work in this area certainly seems warranted. However, given
the significant increase in the disease and the ethical problems
raised by the use of tissues taken from aborted foetuses, it would
clearly be preferable to have stem cell lines which are able to
form dopaminergic neurons.
This is the aim of the Dance (Development of Human Dopaminergic
Neuronal Cell Lines for Transplantation) project. 'Our aim is to
create cell lines able to be produced on an industrial scale, offering
better quality guarantees and which we could make commercially available,'
explains Lars Wahlberg, a researcher at a small Danish biotechnology
company and project coordinator. 'The neurons we are obtaining at
present do not possess the right characteristics, but progress has
been rapid and we hope to reach the clinical trials stage within
the next three years.'
Another pathology, another strategy, another research
project... The one coordinated by Monique Dubois-Dalcq (of the Institut
Pasteur in Paris) is seeking a cure for multiple sclerosis, an illness
caused by the destruction of the protective layer (myelin sheath)
which partially covers neurons. We know that neuronal stem cells
can sometimes migrate far into the brain to repair certain lesions.
Scientists are therefore going to try to produce stem cells with
an increased migration capacity, and also to identify and use the
many chemical signals which trigger and direct this migration.
Many other European studies are concentrating
on stem cell precursors. The Ectins project, for example, would
like to introduce to promising stem cell lines a gene permitting
the sustained in vitro proliferation necessary for industrial
production. But this could be a proliferation which would stop after
implantation to avoid the risk of tumour development caused by the
potential dynamism of stem cells.
Researchers working on the Neuropair project are
concentrating in particular on the various signals which determine
the destiny of a given neuronal stem cell (especially as it has
just been discovered that these cells can create cell types very
different to their original nerve tissue).
Of course it is not possible to pursue research
in all the various directions without considering their means and
objectives. Two of the 15 European projects are devoted to ethics.
The researchers responsible for these projects will have to meet
the various parties concerned by these technologies, compare their
different opinions, examine what they have written, then publish
certain opinions - all in the interests of organising the necessary
For its part, the Commission has already
assembled a European Ethics Group which, in November 2000, produced
setting the limits within which research on stem cells should take
place. It is known that the work financed by Europe during the next
framework programme will exclude reproductive and therapeutic cloning,
as well as the creation of embryos for research purposes.
As further studies are carried out, so it will be necessary to further
pursue the debate. Society must be informed and, as far as possible,
consulted on the choices made. This is indeed the purpose of the
conference and debates organised by the Commission in December.
Above all, it is the necessary condition to ensure that there is
no divide between the general public and researchers, as any such
split would be damaging to all concerned, especially the patients
who are anxiously awaiting concrete progress in treatment.
Some genetic blood diseases
can be detected at a very early stage of pregnancy,
most notably the rare disorder which forces children
to live in a virtual bubble due to a severe immunodeficiency.
It is usually treated a few weeks after birth by means
of a bone marrow transplant.
Rhodri Jones of the Queens
Medical Centre in Nottingham (UK), coordinator of the
Enfet project, is trying to perfect an alternative treatment:
'In some cases, it is possible to introduce about 1
ml of a solution containing stem cells into the foetus'
abdominal cavity. The operation is carried out in
utero, guiding the needle by ultrasound. At this
very early stage (13 weeks), the child does not yet
have any real immunity. He learns to recognise the (exogenous)
cells as if they belonged to him and produces no rejection
action.' In theory, this would provide a means of avoiding
the generally invasive treatment that infants suffering
from this disease are currently exposed to, namely several
weeks in a sterile bubble, a preparatory course of drugs,
surgery and then the administration of immunodepressors.
About 35 transplants
of this type have been carried out worldwide, most of
them in Europe. They were not all successful, but the
oldest patient is now aged 11. A genuine know-how has
therefore been acquired which needs to be enriched with
new knowledge of stem cells with a view to generalising
The genetic and cellular
processing laboratory at the Inserm's unit 427.It
is here that the cells injected into 'bubble
children' are prepared. (c)INSERM/L.MEDARD