18. April 2006 14:57
Stem cells: between fact and fantasy
Brain cells tested in car-manufacturing plants, frog extracts to aid cloning, and new teeth for toothless gums. All these projects have stem cells in common. The first EuroSTELLS conference held in Venice, Italy (19-21 March) brought together EUROCORES-funded scientists to debate these and other findings from this emerging field, in a realistic and sensible way.
Stem cells, some say, are the future of medicine. Instead of drugs or the surgeon’s scalpel, stem cells could become the body’s own repair kit. But the wildly optimistic claims of ‘cures tomorrow’ are quickly retreating from view. Today, as scientists emphasise how much they still have to learn about these cells, the field has taken a dramatic turn towards basic research.
To reflect this shift, and to encourage the development of a stem cell ‘tool box’ the European Science Foundation launched the EuroSTELLS programme in July 2005. “People applied for ESF funding not as individuals but as networks – in collaborative projects of at least three different countries. This meeting is a unique opportunity to bring these networks together,” commented Mariana Resnicoff, EuroSTELLS programme coordinator. “The point is to encourage synergy.”
The conference attracted scientists from 21 research groups in 11 different countries. Discussions ranged from the immediately practical, including the creation of a stem cell bank, to the huge complexity of epigenetic changes. US stem cell researcher Mahendra Rao encapsulated the strength of this Europe-wide enterprise. “A meeting like this would have been hard to organise in the US.”
Stem cells are rare in the bone marrow, yet the success of a transplant relies entirely on these few cells. “We are interested in how we can expand the pool of these stem cells for clinical transplants,” says project leader Elaine Dzierzak, at Erasmus University Medical Center, Rotterdam, Netherlands. Both the microenvironment and genes confabulate to decide the cells’ fate, and Dzierzak’s research is unravelling the signalling pathways that prompt haematopoietic stem cells to repopulate the entire spectrum of blood cells.
Embryonic stem (ES) cells are highly desirable, as they can be turned into any type of tissue: from insulin-secreting cells for diabetics, dopamine-producing neurons for Parkinson’s disease, skin cells for burn victims, heart cells to help repair the damage of a heart attack. Their therapeutic potential is staggering.
One popular way to obtain embryonic stem cells is by cloning or somatic nuclear transfer. The technique involves introducing the nucleus of a somatic or ‘mature’ cell into an empty oocyte. At the stage when the cells grow into a blastocyst, ES cells can be isolated. The resulting ES cells are genetically matched to the original, which makes them a particular asset for transplantation purposes.
Giovanna Lazzari from the Laboratory of Reproductive Technology, in Cremona, Italy has now shown that this ES cell harvesting technique is possible in large animals. Lazzari has grown hefty clumps of healthy bovine brain cells in a Petri dish, starting from embryos obtained by nuclear transfer. The stem cells were isolated from these embryos at the pre-implantation stage. So far, this feat was only possible in mice.
Yet the ethical storm surrounding any technique involving human embryos, even at the pre-implantation stages, shows no signs of abating. One appealing option is to bypass the need to create an embryo altogether, to ‘reprogramme’ a cell to its undifferentiated stage by mimicking the events that take place in a nuclear transfer.
Yuhong Bian from Keith Campbell’s research group at the University of Nottingham, UK, uses an unusual aid: an extract from frog oocytes. It helps the ‘reprogramming’ by stripping all methylation patterns on the DNA somatic cells. Surprisingly, these frog extracts work in every species tested so far, including cows.
If a cloning step is involved, researchers must keep a close watch on changes that inevitably crop up. “In reprogramming a somatic nucleus into a stem cell, you need de-methylated genes but you must not disturb the imprinting,” cautions Cesare Galli from the Laboratory of Reproductive Technologies in Cremona, Italy, and EuroSTELLS project leader.
Most stem cell lines and embryos generated by nuclear transfer are likely to be carrying imprinting defects. Imprinted genes are unusual in that they are marked with the imprint of the parent who contributed them, usually by DNA methylation.
“Cloned animals are frequently abnormal. Dolly was the exception,” commented Robert Feil, from the Institut de Génétique Moléculaire de Montpellier, France, who in collaboration with Pasqualino Loi from the Universitá di Teramo, Italy, is studying cloned lambs.
Feil has found that errors in one imprinted gene: the receptor for insulin-like growth factor 2 gene in cloned sheep are different to the errors found in cloned mice. He concludes that it is impossible to predict which methylation patterns will be lost.
“We will see benefits of stem cells reaching the clinic soon, but not in the way people imagine,” Ernest Arenas from the Karolinska Institute in Stockholm, Sweden predicts. Indeed, embryonic stem cells are increasingly used as a tool in drug development and toxicology, a practice that will result in better, safer medicines.
Swedish company Cellartis AB specialises in providing human embryonic cell lines as tools both for research and drug testing. This university spin off boasts 30 standardised human stem cell lines, which they are now commercialising. “The biggest demand is for toxicity testing,” Raimund Strehl, from the Goteborg-based venture, told conference participants.
Cellartis counts with the US National Institutes of Health, Japanese and European universities and pharma companies among its clients and collaborators. “Assays with embryonic stem cells are proving particularly good for testing embryo toxicity, since they are more applicable to humans than the standard mouse tests,” Strehl pointed out. Heart and liver cells are among the most popular requests.
In a feat of ingenuity, researchers at Rostock University, Germany, have adapted machines from the car-manufacturing industry to screen for drugs that might influence human neural stem cells. The Baltic Initiative, led by Arndt Rolfs, has collaborated with BMW and Mercedes Benz to transform high throughput automated systems for testing paint into cell-based assays. “It’s an artificial system but we have proof that it works,” says Rolfs. They have already screened small molecule libraries and found more than 30 promising compounds that induce dopamine production in neural stem cells.
The EuroSTELLS meeting also aimed to forge links with other initiatives. Glyn Stacey from the UK Stem Cell Banks explained: “For the clinic, products from stem cell lines may need to be treated as a combination of a transplant and pharmaceutical product.” This repository is an attempt to supply well-characterised cell lines both for research and clinical applications. But how long will it take before stem cells become a therapeutic option? “The timescale from discovery to the clinic of a typical biological medicine can be 25 years,” Stacey said. “It could be at least 20 years before the use of differentiated human embryonic cells are part of routine clinical procedures.”
It is possible that stem cells could one day enable people to grow new teeth, as stem cells have been isolated from the pulp of extracted wisdom teeth. “I don’t believe in the close future you can compete with dental implants,” cautions Szabolcs Felszeghy from the University of Helsinki, Finland. The researchers are intent on identifying the signalling networks that keep these stem cells active in adult mice.
Among the conference participants, prevailed a feeling of relief. “The hype is over. Now people are doing those experiments that should have been done three years ago,” reflected Hannu Sariola from University of Helsinki. The unique properties of ES cells must be understood first, that is surely the key to success.
Contact
Mariana Resnicoff
Tel: +33 (0)3 88 76 71 77
Fax: +33 (0)3 88 37 05 32
