Valina Dawson on preventing cell death in the brain:
What does your lab study?
DAWSON: We study how stroke and neurodegenerative diseases cause cells to die. We want to know the signaling mechanisms that commit neurons to cell death with the idea that along that signaling cascade we should be able to find drugs that could intervene and would help keep cells alive.
Many studies have failed to develop drugs for stroke and neurodegenerative diseases. We thought that if we were ever going to find treatments for human disease we have to figure out why drugs work great in mice, but not in people.
The mouse brain is mostly gray matter (or neurons) with a little bit of white matter (or glial cells) and the human brain is exactly opposite with almost 70 percent glial cells and 30 percent neurons. We may have biased our experimental systems really to protect the gray matter and to ignore the white matter. We decided to learn how to enhance overall brain survival rather than blocking cell death.
How did you go about doing this?
DAWSON: We took advantage of the phenomenon called preconditioning, where you can experimentally and sub-lethally stress a tissue. This stress causes certain genes to be turned on and proteins to be made so that between 16 and 24 hours later, when you expose the tissue to what should be a lethal stress, none of the cells die. This indicates that there are built-in survival pathways that we don't know about.
We examined tissue that had been preconditioned to see which genes were turned on in response to sub-lethal stress. We then tested these genes for their protective abilities by turning them on at high levels in mice. After exposing them to lethal stress, their brains were fine.
Why does this happen?
DAWSON: There is a lot about this phenomenon that we don't understand. It lasts usually for about 72 hours then it dissipates. There must be some reason that we don't operate at this heightened state of protection -- it is just an emergency response -- but by trying to understand what the proteins do we may be able to develop new therapeutic targets, that protect the whole brain.
Did you come up with any promising targets?
DAWSON: We have 60 genes in the freezer and currently are working on five of them. We decided to focus and limit our efforts to just those genes involved in the protective response.
One gene we named Iduna. She is Norse goddess that guards the golden apple tree that cures the gods and goddesses when they are sick or injured. All the other gods from classic Greek and Roman mythology have been used to name other genes, so we turned to Norse names. We have another project going on with a gene we named Thorase after the Norse god Thor.
Do you have any other projects in the works?
DAWSON: These 60 genes will probably provide a lifetime of research projects. But, we will go and look at human neurons derived from stem cells to find out what molecules and proteins are important in the human cells, compare it to our rodent experiments and focus on the genes that are common between both screens.
--Interviewed by Vanessa McMains
Valina Dawson on studying cell survival and death in human neurons:
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