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image European Research News Centre > Medecine and Health > Stem cells: promises and precautions
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image image image Date published: 18/12/2001
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RTD info 32

 

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  Europe seems determined not to miss the stem cell train. The European Union already funds - to the sum of 27.4 million euro - 15 research projects involving 117 laboratories in countries from Finland to Portugal. The next framework programme (2002-2006) will see efforts stepped up even more.
   
     
   

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 complications.
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 babies.

The umbilical cord solution

'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 marrow sample.

Genetic applications

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.

The neuronal aspect

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 (dopamine).

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.'

Multifaceted research

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).

Ethical research

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 debate.

For its part, the Commission has already assembled a European Ethics Group which, in November 2000, produced a document 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.


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Delivering bubble babies

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 technique.

The genetic and cellular processing laboratory at the Inserm's unit 427.It is here that the cells injected into 'bubble children' are prepared.

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

 
     

 

 

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Osteochondral construct - biodegradable scaffold seeded with human stem cells differentiated into cartilage cells (top layer) and bone cells (stained purple in lower layer).

Osteochondral construct - biodegradable scaffold seeded with human stem cells differentiated into cartilage cells (top layer) and bone cells (stained purple in lower layer).
Project Bites (Biomechanical interactions in tissue engineering and surgical repair).

 

Triple labelling images of 'epigenetic' neural stem cells grown in aggregate culture. In blue is the cell nucleus, in green is nestin (neural stem cell marker), in red is GFAP, a marker of astroglia but also expressed in some neural stem cells. Ectins project.

Triple labelling images of 'epigenetic' neural stem cells grown in aggregate culture. In blue is the cell nucleus, in green is nestin (neural stem cell marker), in red is GFAP, a marker of astroglia but also expressed in some neural stem cells. Ectins project.

 

Région cérébrale d'un patient atteint de la maladie de Parkinson. Trois corps dits de lewi (l'un situé au centre, très caractéristique) confirment le diagnostic de cette maladie. C'est dans ces corps que l'on trouve du fer et de l'aluminium en quantité anormalement élevée. ©INSERM/E.HIRSCH

The region of the brain that deteriorates among sufferers of Parkinson's disease. Three Lewy bodies (one very typically located at the centre) confirm the diagnosis of the disease. It is these bodies which contain abnormally high levels of iron and aluminium.
©INSERM/E.HIRSCH

 

Stem cells conference website


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