Stem cells in A-T research
Most cells in the body have the ability to reproduce themselves. However, only a few, known as stem cells, are able to generate cells of different kinds. An example of this is the very few cells in the embryo when a child is first conceived, which over time are able to turn themselves into all the different cells found in the body.
While these embryonic stem cells have the capacity to produce virtually any other cell, the stem cells that remain in people once they are born generally only produce a limited range of cell-types related to the organ or system where they are found.
Stem-cell research has two principal directions:
A tool for research
Stem cells have the potential to produce different kinds of live cells, which we could not otherwise have access to for research purposes. For instance, we can’t take cells from the brains of people with A-T to experiment on in the laboratory.
What we can do, however, is take cells from their skin or blood and ‘re-programme’ these to become stem cells. These cells are known as iPSCs (induced pluripotent stem cells). The next stage is to turn iPSCs into neural stem cells, which can produce different kinds of brain cells. The final step is to use these neural stem cells to produce specific types of brain cell.
For A-T, it would be particularly valuable to create Purkinje cells. These are the cells in the cerebellum which for reasons we don’t yet understand die off over time in people with A-T. This loss of Purkinje cells causes the cerebellum to shrink and produces ataxia in the person with A-T.
While producing any brain cell is difficult, making Purkinje Cells is a particularly big challenge. They are among the largest cells in the brain, with a complex tree-like structure. However, when we are able to do this, it should help us understand what it is that makes these cells particularly vulnerable, and allow us to screen for drugs to make them more stable.
Making brain cells in the laboratory is extremely difficult to do, particularly as brain cells are all linked to other cells in an intricate network of different cell types. Indeed we are only just arriving at a point where we have the necessary technological know-how to do this.
An additional problem is that because the ATM protein play such an important role in keeping cells healthy, it is even more difficult to make iPSCs using cells from a person with A-T and then to use them to create other cells.
Around the world, a number of different centres are producing stem cells from people with A-T and using them in different ways. The A-T Society has recently funded a very exciting project to use stem cells to create Purkinje cells in the laboratory. For more information on this, page link
A means of therapy
We know that in A-T, cells in the cerebellum die off, causing ataxia and other neurological problems. If we could get stem cells to the parts of the brain that are affected and use them to create new cells, we might be able to mitigate the effects of the condition. Stem cells in the brain also produce other substances that are protective of cells. This could be another means of helping existing cells survive longer.
There are two potential approaches to this. One is to stimulate existing stem cells in the brain. The problem here is that neural stem cells are not evenly distributed in the brain and there is much that is still not understood about them. Indeed until the 1990s it was thought that brain cells couldn’t be created at all.
The other approach is inject new stem cells into the brain to create the cells that are missing, or to produce factors that help maintain them. The challenges here are about how you obtain the stem cells, how you get them to the right place and how you ensure both that they do not trigger an immune response and that they only produce the type of cells that is required in the quantities that are required
So while both approaches have great theoretical potential, they both still have a lot of problems to overcome before they can become a reality.