Seth Blackshaw on mapping genes in order to find treatments for hereditary blindness:
Your lab studies both the retina, which controls vision, and the hypothalamus, which controls all sorts of behaviors that range from the biological clock, hunger, thirst, blood pressure, blood sugar and mood. Why investigate these two systems?
BLACKSHAW: These two structures really aren't that different developmentally. During embryonic development, the retina emerges from the side walls of the hypothalamus. And, many of the same genes control the blueprints of both structures.
Our overall approach studying the retina and the hypothalamus is very similar too. We constructed high-resolution molecular atlases of the genes that are turned on and off in each of the systems over the course of development. I completed the atlas of the mouse retina as a post-doc at Harvard and we recently published the gene atlas for mouse hypothalamus development from our work here at Hopkins. These atlases give us the genetics parts list that is required to build these structures.
How will you use these atlases?
BLACKSHAW: We've already begun to use the retinal atlas. We rapidly home in on specific genes that are turned on at different points during development. Then, we manually turn certain genes on in the cells of the retina of a mouse when they normally are off or turn them off when they are typically on to see their direct effect on the retina, so we can determine their function. We've studied about 15 genes so far in the mouse retina. About two thirds of these genes turn other genes on and off. The other third are of completely new with no known function. Also, we found some interesting long non-coding RNAs.
What are long non-coding RNAs?
BLACKSHAW: These long non-coding RNAs seem to be a class of RNA with a new function. We found these RNAs are made in certain cell types from DNA but they don't translate instructions to make a protein. About 30 percent of transcription factors -- proteins that turn genes on and off -- in the brain and retina have these RNAs paired up next to the genes that encode the transcription factors. The RNA appears to regulate the activity of its paired transcription factor by controlling its ability to turn other genes on or off. For instance, we found one transcription factor that controls development of the eye and if its paired RNA is removed, the eye fails to develop, similar to what happens when the transcription is removed. The discovery of the function of these long non-coding RNAs is relatively new and we do not know if this method of gene control is unique to the brain and retina.
Of the other genes in the mouse retina that you've examined, do any others have exciting potential for future studies?
BLACKSHAW: One of the transcription factors we identified is important for the survival of photoreceptor cells--the rods and the cones that detect light and allow us to see. We've found that a small molecule binds to this transcription factor enhancing survival of the photoreceptors in mice that have a genetic form of hereditary blindness. We are expanding these studies to see if this small molecule has protective effects in other cells of the mouse retina damaged by other eye diseases. Perhaps, one day drugs can be designed from this molecule that may treat hereditary blindness or age-related macular degeneration in people.
Based on your work in the retina, you believe that we may be able to one day treat hereditary blindness in other ways too?
BLACKSHAW: In the future, we may be able to regrow our retinas like fish and reptiles do. Cold-blooded animals don't stop growing like mammals, and they keep a little pool of stem cells squirreled away for the purpose of adding to the growing retina.
Since we don't have a pool of retinal stem cells, we can't regenerate our retinas. But, we do have a subset of cells in the eyes called the Muller glia cells that are support cells that pass on nutrients to the neurons and remove waste and other byproducts of metabolism. These cells resemble the retinal stem cells in cold-blooded animals in their shape and in what genes are expressed. With a little gene manipulation, we may be able to get these Muller glia cells to turn back into stem cells and then push them to become photoreceptor cells to repair the retina.
--Interviewed by Vanessa McMains