FOCUS Ophthalmology KEEP AN EYE ON IT BREAKTHROUGHS IN THE RETINA BY RISHA CHAKRABORTY AND JOHNNY YUE 16 Yale Scientific Magazine September 2023 www.yalescientific.org
Ophthalmology FOCUS What if you suddenly had blurry vision, couldn't recognize familiar faces, or had difficulty adapting to dimly lit places? This is the reality for people with age-related macular degeneration, also known as AMD, one of the most prevalent causes of vision loss that affects around 200 million people in the world. In AMD, damage occurs in the macula, an oval-shaped area at the center of the retina. The retina consists of a layer of cells known as photoreceptors, which are crucial for converting light entering the eye into signals sent to the brain. The macula is specifically responsible for sharp and central vision. Thus, someone with AMD usually has difficulty deciphering fine details. There are limited effective therapies for the disease— current treatments such as vitamins and minerals only slow disease progression, but do not stop or reverse it. Yale scientists are among those who have joined the cause to find out more about AMD disease pathology. From discovering possible therapeutic targets for AMD and other neurodegenerative diseases to uncovering a quantum chemistry reaction in the retina, their findings could not only inform potential AMD treatments, but also offer applications far beyond the eye. A Window Into Neurodegeneration In a recent study published in Nature Communications, Yale Assistant Professor Brian Hafler and a team of Yale researchers found that AMD, which is itself a neurodegenerative disease of the retina, could serve as a system for understanding other neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis. To arrive at this finding, they developed a novel approach to understanding AMD and its cellular pathology. Hafler and his team utilized single-cell data and machine learning techniques to pinpoint the populations of cells in the retina that play a prominent role in the disease progression of AMD. This study built upon previous research in the retina which highlighted the overall role of inflammation in the pathology of macular degeneration. The team isolated 70,973 individual retinal cells from seventeen different human retinas with different stages of disease and healthy controls. “This allowed us to build a unique When medical research is applied to patient care, we can uniquely translate novel therapeutic approaches for diseases like AMD. road map into the genetic networks driving inflammation in macular degeneration and hopefully to develop new therapeutic targets,” Hafler said. To analyze these cells, the team designed a novel collection of machine learning tools which they termed “Cellular Analysis with Topology and Condensation Homology,” or CATCH. At the core of CATCH is a method known as diffusion condensation, which identifies similar groups of cells based on how they are pulled toward the weighted average of neighboring cells in space. This method enabled the team to pinpoint two populations of activated glial cells (cells whose primary role is to support neurons): astrocytes and microglia. Astrocytes provide neuroprotective, structural, and metabolic nourishment to nerve cells, while microglia are the immune cells of the brain and mount responses to pathogens. Both were found to be activated in the early phase of AMD. Surprisingly, similar activation profiles were found to dominate the early phases of other neurodegenerative diseases, such as Alzheimer’s disease and multiple sclerosis. This association led the researchers to believe that early stages of neurodegenerative disease progression generally utilize a common mechanism involving the activation of glial cells. It also suggests that the retina can potentially be a unique system for developing new therapeutic strategies to treat neurodegenerative diseases. Then, using single-cell data from Alzheimer’s and multiple sclerosis studies, Hafler and his team were able to characterize specific cellular interactions that induce inflammation, which may be a common characteristic of neurodegenerative disease progression. They first identified interleukin- 1β, a protein that signals immune cells to mount and induce a response, that was derived from the microglial cells activated in AMD. Using a computational technique, they found that interleukin-1β signals for astrocyte activation are pro-angiogenic, meaning that they enhance blood vessel formation. This observation lined up with the typical symptoms observed in wet AMD, an advanced stage of AMD. In late stages of AMD, blood vessels can abnormally form, grow, and leak beneath the macula. This bleeding can distort the retina and impair one’s central vision. Hafler’s study suggests that targeting astrocytes and microglia should be further considered when attempting to treat neurodegenerative diseases. Anti-angiogenic medications are currently the primary treatment, but they are only effective in advanced stages of the disease. To fill in the gap, interleukin-1β may be an effective target. With Hafler’s deep understanding of AMD both in a clinical and research setting, his results show promise towards moving forward in the fight against AMD. “My clinical practice is what drives my benchwork in the lab,” Hafler said. “When medical research is applied to patient care, we can uniquely translate novel therapeutic approaches for diseases like AMD.” How Does Melanin Protect The Retina? A second study, published in PNAS, found a quantum chemistry reaction that could explain how melanin protects the retina from age-related macular degeneration. Yale scientist Douglas Brash, a physicist by training and co-author of the study, did not expect to investigate AMD. But one day, he performed an experiment on melanocytes, which are special melanin-producing cells. Melanin is a natural pigment that shows up across the body, from the eyes to the skin. In the skin, melanin accumulates with UVlight exposure. In the retina, melanin exists in tiny granules at the photoreceptor layer; however, its function is almost completely unknown. Brash wanted to see what would www.yalescientific.org September 2023 Yale Scientific Magazine 17
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