BioWorld International Correspondent

LONDON The idea of being able to take someone’s skin cells and turn them into nerve cells to treat a neurological disease in the same person has inched closer.

Scientists based in Norway, in collaboration with the biotechnology company Nucleotech LLC, have discovered that adult skin cells can be reprogrammed so that they take on some of the qualities of immune system cells or nerve cells.

Philippe Collas, of the Institute of Medical Biochemistry at the University of Oslo in Norway and chief scientific officer of Nucleotech, and his colleagues report their findings in a paper in the May 2002 issue of Nature Biotechnology titled “Reprogramming fibroblasts to express T-cell functions using cell extracts.”

Collas said the method described in the paper represents the first in vitro system capable of altering gene expression in adult cells in a straightforward and efficient manner. He told BioWorld International, “This is an entirely new approach to tissue replacement therapy that avoids many of the political, ethical and scientific issues that have confronted this field.”

Scott Fabricant, chief operating officer of Wesport, Conn.-based Nucleotech, said, “The use of our in vitro reprogramming system represents a promising platform for producing a variety of different cell types, a critical step that brings us closer to finding treatments for many diseases that are the result of cell or tissue damage. Our primary goal at this early stage is to develop cell transplant therapeutics for diseases such as Type I diabetes, cancer and heart disease.”

Collas said he and his colleagues are testing whether fibroblasts can be induced to take on the characteristics of dopamine-producing neurons (which could theoretically be used to treat Parkinson’s disease), cardiomyocytes (to treat heart disease), hepatocytes (to treat liver conditions) and insulin-producing beta cells (to treat diabetes).

The group wants to progress to validating the method in relevant animal models, such as diabetic rat and mouse models. “Once we have validated the system in animal models according to U.S. standards,” Collas said, “then we can progress to human clinical trials. But even if all goes well these will be three or four years away.”

He envisages patients being able to visit their local clinic and have a skin biopsy taken that would be sent away for reprogramming into the type of cell required to treat each person’s condition. The cells would then be transplanted back into the original donor.

Azim Surani, professor of developmental biology at the University of Cambridge, cautioned, however, that use of the technique in therapeutics is a long way off. “The evidence provided in the paper suggests that there is some change between the cell they start off with and the cell they end up with at the end of the procedure. But this change is not complete,” he told BioWorld International.

It would be wrong to say that the team had changed a skin cell into a nerve cell, he added. “Furthermore, the kinds of manipulation that are involved in bringing about these changes are quite substantial, so there is no immediate possibility of using this approach in therapy without substantial additional work,” Surani said.

It may, however, not be necessary to convert completely one cell type into another in order to have a therapeutic effect, Collas said. “We may find that we do not need to make, for example, a pure beta cell in order to get the cell to make insulin. Perhaps we need to make only what we are calling a therapeutic cell’ that has the functions that we want it to have. In this case, we may not always need to suppress all original functions of the cell.”

Collas and his colleagues exposed human fibroblasts (skin cells) and fibroblast nuclei to an extract from the nuclei and the cytoplasm of T cells. After the fibroblasts whose membranes had been treated to make them permeable had been exposed to the extract and their membranes returned to their normal state, several genes that would not normally be active in fibroblasts, but which are active in T cells, became switched on. They included the genes encoding the receptors CD3 and CD4, and the receptor for interleukin-2. Further investigations showed that complex intracellular signaling pathways normally found only in T cells were operational in the modified fibroblasts. The changes observed persisted for several weeks following the exposure to the T-cell extract.

The team also explored what would happen if it exposed the fibroblasts to extracts from neuronal precursor cells. Fifteen days later, about 18 percent of the fibroblasts were expressing a protein normally produced only in nerve cells, called neurofilament protein, or NF200. Those cells even produced long, thin outgrowths resembling those made by developing nerve cells, in which the NF200 was localized.

Surani is the joint author of a “News & Views” article on the paper, with Patrick Western, also of the University of Cambridge. The article, which appears in the same issue of Nature Biotechnology, is titled “Nuclear reprogramming alchemy or analysis?”

They conclude that the technique pioneered by the Norwegian/American team “provides a potentially powerful system for analyzing nuclear reprogramming events as they occur in vitro.”

Surani predicted that other researchers now would want to try to reproduce the results, and discover ways of improving the efficiency of the procedure. Collas and his colleagues also are working on determining exactly which factors in the extracts they treated the fibroblasts with brought about the changes they observed.