Week in Review: Number 8

Axonal Regeneration after Silencing a Cytokine Gene
Researchers at Yale University recently identified 40 genes involved in preventing axonal regeneration in the central nervous system in a mouse model. By suppressing those genes, especially the gene for the cytokine interleukin-22 (IL-22), they were able to regenerate retinal ganglion cell axons in a mouse model of glaucoma (by optic nerve crush). The study itself seeks to investigate the larger topic of CNS nerve regeneration, and in this case uses the convenient model of the optic nerve. The authors state, “Reduced IL-22 drives concurrent activation of signal transducer and activator of transcription 3 and dual leucine zipper kinase pathways and upregulation of multiple neuron-intrinsic regeneration-associated genes.” In other words, suppressing this cytokine gene led to favorable expression of regenerative genes. This kind of discovery was facilitated by the advent of DNA cutting technologies, such as the viral-driven short hairpin RNAs used in these experiments; another DNA cutting technology most of us have heard of by now would be CRISPR-Cas9. These gene editing tools allow researchers to observe the function of a gene by silencing it, by rendering the gene nonfunctional through cutting its DNA sequence. The researchers also noted that identifying multiple genes suggests multiple molecular pathways, which could be useful for both multiplexed gene editing (a more efficient method of gene editing) and interventional therapeutics.

Genome-Wide Association Study of Keratoconus
An international team of researchers from the UK, the US, the Czech Republic, the Netherlands, Australia, Austria and Singapore recently conducted a genome-wide association study of keratoconus. The observation that keratoconus is more common in people with an affected relative led scientists to consider a genetic link. The present study compared the full genome of 4,669 people with keratoconus to that of 116,547 people without keratoconus, a larger sample size than in previous studies for the condition in question. The team found an association between keratoconus and defects in corneal collagen matrix integrity. They also found possible abnormalities in the cell differentiation pathways of corneal cells in keratoconus. Though the sample population severely lacks ethnic diversity, a not uncommon situation, the data still contributes to collective knowledge overall. The researchers hope that the genetic information can help pinpoint a biological mechanism for the disease, in turn guiding early detection and intervention. Currently, the only treatment for keratoconus (short of corneal transplant) is corneal crosslinking. Genetics, and other methods for early detection, could help initiate therapy before the disease progresses to affect vision.

Macrophages of the Human Eye Come into Focus
Macrophages are immune cells present in all ocular tissues. On the surface of the retina they look and act like microglia, the "sentinels of the central nervous system." The present study using ocular coherence tomography (OCT) and adaptive optics (for enhanced image resolution) is the first to visualize these cells in real time in the eyes of living humans. The imaging technique allowed the researchers to pinpoint the location of retinal macrophages. For example, they discovered that in healthy eyes, the macrophages were densely distributed in the periphery of people's retinas and sparsely found near/at the fovea. The researchers hypothesized that the relative absence of macrophages at the fovea is related to retinal development, wherein photoreceptors migrate to what becomes the fovea, and the inner layers of the retina (such as the ganglion cell layer and nerve fiber layer) move aside for clearer light transmission. The role of macrophages is to clean up cellular debris from the inner retinal layers, which are absent at the fovea, and thus might explain macrophages' absence there. The researchers also found that in glaucoma, macrophages gather in areas of active disease. If these changes can be visualized and monitored over time, they could be an avenue of research as a biomarker of disease activity and severity.

AI Models for the Study of Motion Perception
Researchers at the University of Cambridge have developed an artificial neural network to study motion perception. Called MotionNet, this computer network simulates a particular type of visual processing known as the reverse phi phenomenon. In the phi phenomenon, which most of us are familiar with in the form of animated films, dark spots appearing in succession give the illusion of motion. In the more perplexing reverse phi phenomenon, if the second point becomes light rather than dark, then we perceive the motion as moving in the opposite direction; instead of perceiving the sequence moving "forward," we perceive it as moving "backward" (keeping in mind that directions are relative). The MotionNet system seems to faithfully replicate the mistakes that human brains make with regard to the reverse phi illusion, but has the advantage of being able to be examined and tested in detail. The researchers found, for example, that the reverse phi illusion triggered "neurons" in their system that were tuned to the direction opposite of the actual movement. The system also revealed information about the speed of movement and spacing of dots on the effect of motion perception. Studying optical illusions has consequential implications for patient care beyond scholarly interest. For example, in previous work, the researchers showed that neurons in our brain are biased towards slow speeds, so when visibility is low we tend to think that objects are moving more slowly than they actually are. These findings are thus applicable to real-world scenarios, such as accurately gauging the speed of moving objects when driving in low visibility conditions. The MotionNet artificial neural network is a model wherein preliminary experiments could provide insights for more focused studies in subsequent biological models and human subjects.

Windows of the Brain: Retinal Screening for Early Detection of Neurodegenerative Diseases
This article is an example of coverage about eye care that appears in everyday news, in this case in the Washington Post, to inform the public and patients about the importance of being vigilant about their health in general and their eye health in particular. This article addresses the value of early detection in neurodegenerative diseases, such as Alzheimer's and Parkinson's, to improve treatment outcomes or interpersonal arrangements. Progress in retinal screening has great potential to provide a noninvasive and relatively inexpensive window to neurological health. The article highlights three projects toward this goal. The first by neuroscientist Maya Koronyo-Hamaoui at Cedar-Sinai visualizes beta amyloid plaques, a hallmark of Alzheimer's disease, through ingested curcumin (a compound in turmeric), which has high affinity for beta amyloid and shows up on retinal exam (with the right fluorescence-detecting equipment). The second project by biomedical engineer Ruogu Fang at the University of Florida uses smartphone fundus photography and artificial intelligence algorithms to screen photos of the microvasculature of the retina, on the premise that there is strong correlation between hypoxia and neuronal death characteristic of both Alzheimer's and Parkinson's. In a third project that also uses a neural network and ocular coherence tomography (OCT), vitreoretinal surgeon Sharon Fekrat at Duke University found that thinning of the retina's ganglion cell layer is highly predictive of Alzheimer's diagnosis. These techniques are not flawless, since the association between biomarkers and disease is complex. Nonetheless, with increasing sensitivity, they undoubtedly become more valuable tools in the diagnostics armamentarium.

In Other News
(1) Eyeless C. elegans perceives colors (Related)
(2) Probing the mysteries of ophthalmic migraines
(3) Photokeratitis risk in UV light disinfection