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Making myelin in a dish.

Making and maintaining the myelin sheath that surrounds the axons of neurons involves cross talk between axons and glial cells. One approach to studying this complicated process is to culture neurons and glial cells in a dish. It is then relatively easy for researchers to change environmental factors or to apply possible therapeutic chemicals to the dish of growing cells. In this way, scientists hope to work out how myelin is made and to solve the clinical problems arising from errors in this process.

All cells interact with each other through a limited number of known signalling receptors: proteins acting at the surface of the cell. So when cross talk happens between axons and glia during myelination it’s a good bet that some of the known signalling pathways are involved. However, things then get more complicated. Signals travel from the surface of the cell through a host of different intermediates to the nucleus at the centre of the cell. This is where genes are found. The intermediates make contact with the genes and affect their activity: the making of proteins. Our task is to find which pathways are being used when axons and glia talk to each other and at what point things are going wrong in a neural disorder. How can we do this?

For many years now, pharmaceutical companies have generated chemical libraries of small



molecules which they apply to cells in culture looking for effects on chemical pathways within the cells that might be of clinical use. Now scientists are using these libraries to investigate the molecular pathways involved in myelination. The small molecules are added to cultures of neurons and glial cells in a dish. They can be added at different concentrations and times much more easily than in the whole animal. If the neurons or glial cells are taken from a diseased animal or human, then we are looking for molecules which will correct the mistakes. Molecules with relevant activities can be identified, usually from a large pool of candidate molecules. The next step is to pinpoint and purify the member of the pool carrying the desired activity. The molecule can then be tested therapeutically in animal models.

The details of where and when the molecule acts can be determined in the whole animal and this is likely to mimic what happens in human disease. Often basic research in animals or clinical observations arising from disorders in humans gives us a clue to which pathway is affected in a disorder. This narrows down the search for therapeutically active molecules because sub-libraries specific to a single signalling pathway are available.

Chemists have identified certain ‘favoured chemical structures’ which have biological activity when applied to cells in culture. These structures can be imagined as a tree. There is a common backbone (the trunk) to which various chemical groups may be added (the branches). All these structures have similar biological activity but certain branches may increase the activity. This, of course, is clinically helpful. You can use much less of the compound to produce the same effect and toxic side effects may be avoided.

So the application of small molecules to neurons and glia in culture, together with studies in animal models hold the promise of finding clinically useful therapies for the many neuropathies which result from mistakes in myelination.