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Friday, September 18, 2009

Color Blindness, Gene Therapy & Brain Plasticity

Prologue
In my post dated May 28, 2009, I wrote about the squirrel monkey Miss Baker. She was the first primate to successfully complete a space voyage half a century ago. Yesterday, two other squirrel monkeys, Dalton and Sam, accomplished another first. That is, they were the first to successfully undergo gene therapy, repairing color blindness.

Our color vision is provided by photoreceptor cells in the eye's retina known as cones. Three types of cones have been identified. Each type is particularly sensitive to either blue, green, or red light, depending on the molecular structure of their photopigments known as opsins. While two copies of the gene encoding the blue-sensitive opsin are located on a pair of somatic chromosomes, the genes for green and red exist in only one copy on x chromosomes. If they are damaged, we are not able to distinguish between green and red. Particularly males are vulnerable because a spare is unavailable. Thus, color blindness affects 8 percent of white men, but less than 0.5 percent of white women. By contrast, most male new world monkeys, including squirrel monkeys, are color-blind.

The Therapy
Yesterday, Katherine Mancuso and her colleagues published a letter in the journal Nature online in which the authors provide evidence that two adult male squirrel monkeys, Dalton and Sam, gained color vision within about half a year after they had been treated with gene therapy (Mancuso and others, 2009). That is, their eyes had been injected with an engineered virus encoding the missing long wavelength-sensitive opsin or green fluorescent protein (GFP). The recombinant DNA was supposed to be inserted into cone DNA. The GFP served as an independent marker for successful insertion. The hope was that the cones with the engineered DNA would synthesize the missing opsin, eventually enabling the monkeys to see differences between red and green.

Dalton and Sam were experts in visual discrimination tasks. They had been trained in a modified Cambridge Colour Test before the intervention and were experienced participants. The test consisted of colored dot patterns embedded in gray dots similar to tests with numbers or letters laid out in colored dots for people. Dalton and Sam began to distinguish red and green in the sixth month after the virus injection.


The authors monitored retinal function using wide-field color multifocal electroretinography. This type of electrophysiological recording describes stimulus reception, transduction and processing in the retina. Retinal responses to red were undetectable four months after the intervention, but had risen to prominence at ten months and were further enhanced at 18 months. At that time, the monkeys could distinguish between 16 hues of red and green. GFP was expressed in roughly 15–36 percent of the cones. Taken together, the findings of this study constitute a promising prove of concept for the great potential gene therapy may hold for the restoration of retinal function.

Brain Plasticity
The question remains how Dalton and Sam could correctly interpret visual cues they had never seen before. Could the nerve cell connections in the visual system reorganize on a scale required to process the novel sensory input?

Around 1960, the Nobel Prize-laureates Torsten Wiesel and David Hubel had discovered that the cerebral cortex reorganized profoundly in response to sensory deprivation in a limited window of time during brain maturation. Primary visual cortex consists of interdigitated domains in which neurons respond mainly to input from one eye. In their pioneering study, Wiesel and Hubel occluded one eye in newborn kittens and observed that the other eye's cortical domain enlarged into the deprived territory (Wiesel and Hubel, 1963). The effect could be reversed, if the eye occlusion was reversed within a critical period. Reversal in adults had no effect. Much research ensued to uncover the underlying mechanisms.

By contrast, Dalton and Sam were adult at the time of the intervention. The authors took their findings to suggest that the visual system remains highly plastic even in maturity. However, compared with monocular deprivation color-blindness seems to pose a minor challenge to the visual system. In the gene therapy study, the neural circuitry necessary for color discrimination may have already been in place at the time of the intervention. Existing connections may have only needed strengthening to attune the neurons to the novel inputs, precipitating the monkeys' correct decision in the test. It is puzzling, however, that it took the monkeys months to improve the new skill.

To better understand the neural mechanisms involved in the monkeys' novel ability to discriminate color, it is crucial to find out precisely when after the intervention the photoreceptors become sensitive to new wavelengths of light.

References
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