Editor's Note: This is part two of a three-part series on global stem cell research. Part one ran in Wednesday's issue. Part three will run in Friday's issue.

The most widely read Swedish author is Astrid Lindgren, whose creation Pippi Longstocking would have made a great scientist: She's smart, curious and, most importantly, irreverent.

Peer-reviewed literature has a smaller market than Pippi, who has sold millions of copies in dozens of languages. But Swedes also are at the top of that game: They consistently publish the highest number worldwide of peer-reviewed scientific and technical articles per 100,000 people, and the country has a framework favorable for stem cell research, making them a European leader.

Opponents of embryonic stem cell research sometimes point to adult stem cells as proof that the benefits of stem cells can be had without the ethical quandaries associated with embryonic stem cell research. Most scientists, including most adult stem cell researchers, would insist that what is unknown about stem cells still is a vast territory, and cutting off any avenue of research would be premature.

Anders Bjorklund, head of the Swedish section of EuroStemCell, a pan-European research effort to investigate types of stem cells and their potential for treating degenerative diseases, is one of those scientists who believes pursuing multiple avenues is key. Bjorklund is something of an elder statesman of stem cell research, having worked in the field since the 1980s. He is a basic researcher and pioneered fetal stem cell transplants for Parkinson's disease in animal studies. That research eventually led to human clinical trials, all of which have to date used tissue from aborted fetuses.

Such transplants showed proof of principle that they could alleviate the symptoms of Parkinson's, though more recent double-blind studies in some cases have missed their primary endpoints, and involuntary movements, as a consequence of too much dopamine release by the transplanted cells, have been observed regularly. That highlights one of the issues of cell transplants: After the original transplant, it is very hard to adjust the dosage.

Bjorklund noted that while the most interesting experimental results have been obtained with mouse embryonic stem cells, those cells also have particularly strong safety issues, because they are tumorigenic.

Which of the stem cell types ultimately will give the best results "would be difficult to say at this point," Bjorklund told BioWorld Today. "That's why it's good that research progresses along parallel lines."

Investigating Stem Cells To Alleviate Allodynia

Sweden's high-quality research was illustrated most recently in the March 2005 issue of Nature Neuroscience, in which scientists from the Karolinska Institute in Stockholm, with colleagues from the University of Oxford and the Medical College of Wisconsin in Milwaukee, published a study on the transplantation of adult neural stem cells after spinal cord injury.

As if to add insult to that injury, besides the loss of sensation, one frequent consequence of spinal cord injury is allodynia, in which previously benign stimuli become painful.

"Some studies estimate that approximately 65 percent of all human victims suffer from chronic pain conditions," lead author Christoph Hofstetter told BioWorld Today. "In our animal model, spinal cord injury itself already started the development of allodynia. Transplantation of adult neural stem cells caused a dramatic aggravation of this condition."

Based on previous research, Hofstetter and his colleagues suspected that the proliferation of astrocytes, a type of support cell in the nervous system, might indirectly be responsible for the development of allodynia. To test their idea, they transplanted into rats that had sustained a spinal cord injury that affected motor control of their hindlegs, but not their forelegs, either regular adult neural stem cells (isolated from the spinal cords of other rats) or adult neural stem cells that had been manipulated to express a surface molecule that suppressed astrocyte development.

Instead, a greater proportion of the stem cells developed into oligodendrocytes, another type of support cell that forms the insulating sheath around neurons that allows them to transmit electrical impulses over long distances.

The scientists found that while both types of cell transplants improved feeling and motor functions of the hindlegs, the manipulated cells led to greater improvements than the unmanipulated ones by nine weeks post-transplantation. Animals treated with the manipulated cells also showed less hypersensitivity in their forelegs to non-painful stimuli.

Hofstetter said: "The message of the paper is that the whole variety of cells, which can be generated by stem cells, is not necessary for spinal cord injury repair. Transplantation of cells that are able to ensheath axons seems to be a good treatment approach for incomplete spinal cord injuries."

Hofstetter also said that his group has no plans to commercialize the research, but the commercial applications of adult stem cells are also being pursued in Sweden, by Stockholm-based NeuroNova AB.

Although NeuroNova itself was not specifically involved with the research in the paper, one of its co-authors, Jonas Frisen, also is co-founder of the company, which specializes in the commercial potential of adult stem cells. The company is active both in therapeutic neurogenesis and cell therapy.

Therapeutic neurogenesis is the stimulation of endogenous cells to generate new neurons, via therapeutic proteins (delivered either into the cerebral ventricles or systemically) and small molecules. NeuroNova is pursuing therapeutic neurogenesis to treat orphan indications, cognitive impairment, Alzheimer's disease, Parkinson's disease and stroke. Cell therapy is the transplantation of cells that can functionally integrate into the existing neural circuitry, and the company intends to commercialize cell therapy for Parkinson's disease and spinal cord injury.

Karolinska Institute's Hofstetter echoes Bjorklund on the relative merits of different types of stem cells.

"The idea of using adult stem cells is that they could be potentially used for autologous transplantation, i.e., cells are harvested from the patient, expanded in culture and then transplanted back into the same patient. This would be ideal since there would be no risk of graft rejection or infection of the host by contaminated cells," he said. "However, research with embryonic stem cells is a necessary tool to eventually understand stem cell biology and then use it to direct adult stem cells for safe treatment strategies."