Swiss OphthAward for D-BSSE Postdoc Michele Fiscella

To and fro, to and fro: If you watch someone's eyes while watching a train passing, the eyes follow the train and then flick back to the starting point. This is repeated over and over until the train has passed. The eyes adjust to give us the best vision possible; this is how our eyes work. The so-called optokinetic reflex causes eye movement in response to objects moving while the head is stationary.

Rapid and uncontrolled eye movements, also called "dancing eyes", are observed in people that suffer from "nystagmus" - a severe eye disease. The involuntary movements are usually sideways but can also be up and down or, rarely, include a circular motion. There are two main types of nystagmus: One which appears in the first months of life, which is called "congenital nystagmus" and another type, which develops later in life, the so-called "acquired nystagmus". Most people with this eye disease have reduced vision, but nystagmus does not result in total loss of vision -  fortunately - since this disease cannot be cured.

Nystagmus can develop if the visual pathways or parts of the brain that process visual information and control eye movements do not develop properly or are damaged in later life. In about 70 % of the cases the culprit has now been identified: A gene sitting on the X chromosome called FRMD7. However, how a defect in this gene finally leads to the disease has remained unknown.

Therefore, researcher teams around the world are looking at different aspects of nystagmus with the aim of developing treatments. One of them, consisting of the groups of Professor Botond Roska at the Friedrich Miescher Institute (FMI) and of ETH Professor Andreas Hierlemann, has now been awarded for their research: Keysuke Yonehara, Antonia Drinnenberg and Michele Fiscella received the Swiss OphthAward in the category "Best Experimental Work" at the annual meeting of the Swiss Society of Ophthalmology in Interlaken. They received the award for their paper titled "Congenital Nystagmus Gene FRMD7 is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity", published last January in the journal Neuron. One of the first authors, Michele Fiscella of the ETH team comments on the award: "Our experimental results published in Neuron span across several disciplines, including, for example, genetics and computer science. The Swiss OphthAward is a confirmation that interdisciplinary work is the key factor for successful research. Since 2008, I have been collaborating with the Roska group working at the FMI in Basel. I have been mainly involved in large-scale cell experiments and I have studied the electrical signals that the eye sends to the brain. I particularly focused on retinal cells that are involved in detecting the direction of moving objects."

Engineered by the group of Andreas Hierlemann at the Department of Biosystems Science and Engineering of ETH Zurich in Basel, a microelectronic chip allows to study retinal cells, to be precise, the electrical activity of retinal ganglion cells. The CMOS-technology-based high-density microelectrode array also enables to analyse visual computations performed by the retina with unprecedented precision. Thus, the neurobiologists have been able to record and measure the electrical signals of thousands of ganglion cells simultaneously, as the retina processed the movement of objects. As Michele Fiscella explains: "The retina is located in the back of the eye. The role of the retina is to convert a visual scene into electrical signals for the brain. These electrical signals can be recorded by the CMOS-based system developed at ETH Zurich, and further analysed to understand visual computations performed by the retina." He scanned a series of retinas obtained from transgenic mice, carrying gene mutations potentially linked to human eye diseases. "The retina can be isolated from the eye and kept alive on the CMOS system for up to 12 hours."

Fiscella and the co-workers of the Roska group identified a clearly defined neuron type in the pathophysiology of the eye disease congenital nystagmus: The FRMD7 gene is implicated in the establishment of cell connectivity among retinal neurons. Mutations in the FRMD7 gene disrupt the correct wiring among these retinal neurons, thus resulting in a disease of vision and functional loss: The retinal cells are no more capable of detecting objects that are moving horizontally. The reason is a defect in starburst cells, elicited by the dysfunctional FRMD7 gene, which leads to the loss of the horizontal optokinetic reflex. Fiscella explains: "The FRMD7 gene is expressed in the starburst cell. The starburst cell is a specialised neuron of the retina. It is the key element for detecting the direction of moving objects. The correct wiring between the starburst cells and other retinal neurons is important for detecting the direction of moving objects."

As they published in Neuron, the lack of functional FRMD7 in mice causes the loss of the horizontal optokinetic reflex. "We found that mice were not able to track horizontally moving objects, as it was the case for nystagmus patients. Furthermore, mice were still able to track vertically moving objects, as were patients", Fiscella adds.

Now, the scientists have a valuable mouse model at hand that reproduces symptoms of the human disease and reveals a molecular entry point, FRMD7 in starburst cells, to further probe into the molecular mechanisms of this eye disease. As Fiscella concludes: "We have a mouse model representing a human disease. Therefore, we can use the mouse model to test potential therapies aimed to restore the FRMD7 gene function also in humans."