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The transcription factor: a key to brain repair?

Ben Martynoga

Ben Martynoga

In the first of the three highly commended articles for the Max Perutz Science Writing Award 2012, Ben Martynoga describes his research looking at how to reprogram brain stem cells and even other types of cells to become new neurons — research that could one day lead to treatments for brain diseases.

Your skull contains one of the most sophisticated computing systems in the universe. Your brain can read and understand the words on this page, it can empathise with other humans, and it is even aware of its own existence. Nothing we have built or discovered comes close to this competence. Yet brilliant as your brain is, it has one fatal flaw: it is terrible at regenerating itself.

Cut your hair and it keeps on growing. Cut your skin and it rapidly heals. But once a brain disease like Alzheimer’s disease sets in and starts to kill off your brain cells, the damage gets progressively worse, with devastating effects. And of course, as our families and communities live longer, age-related dementia and memory loss are ever more common.

Wouldn’t it be amazing if your brain, more like your hair and skin, could go on replacing damaged or lost cells throughout your life? In my research I want to understand how the cells in the brain function with the hope of making this possible.

Scientists are already able to take cells from a mouse’s brain and grow them so they go on dividing and replacing themselves forever. These cells are a type of stem cell. It’s hard to know what gives stem cells their unique regenerative abilities. My work on these cells should help future doctors use stem cells to replace brain cells lost through damage or disease.

All cells contain the same set of genes. So the fundamental difference between a skin cell and a brain cell is not which genes they possess, but which genes they actually use. The process of turning specific genes on and off is achieved by tiny switches within cells which we call transcription factors.

Just as putting the correct combination of words into a Google search query delivers the result you are looking for, putting the correct combination of transcription factors into a cell activates the genes needed for that cell to work properly.

By experimenting with lots of different transcription factors I have identified a small number that act together to stimulate brain stem cells to multiply.

So how might this knowledge actually help us to treat anyone? There are two main possibilities. The first is using the transcription factors to control the activity of existing brain cells. Although they are very rare our brains do contain some stem cells that are able to multiply themselves and make new brain cells, but as we get older they fall dormant. By understanding the combination of transcription factors unique to multiplying stem cells we have the potential to activate dormant brain cells when and where they are needed.

The second possibility is even more remarkable. We can use these same transcription factors to totally transform one type of cell into a completely different type. For example, scientists have already succeeded in converting skin cells into brain cells. This has radical implications. Theoretically it should be possible to take a sample from a patient’s skin and create new brain cells on demand. Since these cells come from the patient themselves, they are more likely to become properly integrated and less likely to be rejected.

However, at this stage more knowledge is still required before these techniques reach clinical trials. In the first technique, we still need to learn how to control which dormant cells become activated, and perhaps even more importantly, how to stop them. Unless we can do this there is a risk that brain tumours would develop. This is also a risk of the second technique, which also comes with the added complication that it is very difficult to be sure that exactly the correct type of brain cell has been created before they are actually transplanted.

Your brain is undoubtedly the most complicated organ in your body. This is what gives it its extraordinary power. However it is also what makes it so enormously difficult to treat. We can’t currently predict when these techniques will be ready for use, but the work that I am doing, with colleagues all around the world, is undoubtedly key to making brain repair a reality.

Ben Martynoga

Ben is a postdoctoral researcher at the MRC National Institute for Medical Research.

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