Week in Review: Number 17

CYP39A1 Gene Confers Cholesterol Homeostasis Against Exfoliation Syndrome & Glaucoma
Singapore scientists conducted a genome-wide association study of exfoliation syndrome involving more than 20,000 participants from 14 countries across Asia, Europe, and Africa. Characterized by abnormal proteins in the anterior chamber of the eye, exfoliation syndrome is a major cause of glaucoma as these proteins accumulate in the trabecular meshwork and obstruct the normal flow of aqueous, leading to elevated intraocular pressure and subsequent optic nerve damage, i.e., glaucoma. According to the researchers, although exfoliation syndrome is the most common cause of glaucoma, little is known about the origins of the exfoliative material and the pathology of the disease. The research team identified genetic mutations in the CYP39A1 gene as being strongly associated with increased risk of exfoliation syndrome. People with exfoliation syndrome are twice as likely to carry damaging mutations to this gene. The CYP39A1 gene in particular encodes for the processing of cholesterol, which in turn is a major component of cell membranes. The researchers found that the epithelial cells of the ciliary body, responsible for producing aqueous humor as well as provide a barrier between the blood and the aqueous, were most affected by mutations in the CYP39A1 gene. When the blood-aqueous barrier is compromised, proteins from the blood can leak into the anterior chamber and accumulate, notably, in the trabecular meshwork. The presence of normal CYP39A1 thus has a significant stabilizing effect on cholesterol homeostasis, resulting in an intact blood-aqueous barrier that prevents leakage of exfoliative material into the anterior chamber.

Instrument for Detection of Carotenoids in the Eye
Originating as technology to measure how octopuses see polarized light, researchers in the U.K. then adapted the technology to develop a device that measures levels of carotenoids in human eyes. When tested on humans, the researchers found that people are able to see polarization patterns when the light was only 24% polarized. Humans can see polarized light due to birefringence of macular pigments such as the xanthophylls/carotenoids lutein, zeaxanthin, and meso-zeaxanthin in the radially arranged retinal nerve fiber layer of Henle. Birefringence is the refracting of light into two components, perpendicular to one another, and each having a different refractive index. The retardation of polarized light due to birefringence as a result of the thickness of the RNFL can be detected by ophthalmic instruments such as scanning laser polarimeters (GDx). Macular pigments play an antioxidant role in protecting the retina from ultraviolet light, which helps to prevent or delay retinal diseases such as age-related macular degeneration. Carotenoids are derived from food, thus the detection of the amount of macular pigment in the retina can help clinicians provide recommendations about consumption of foods containing carotenoids or wearing sun protection when outdoors. The lead researcher thinks that while there are existing methods to measure a person's amount of macular pigments, those techniques are time-consuming or expensive. His start-up company seeks to develop a device that enables rapid screening as part of regular eye exams.

Artificial Intelligence with Adaptive Optics Aids in the Detection and Treatment of Glaucoma
Biomedical engineers recently made progress in ophthalmic imaging through combining deep-learning artificial intelligence with optical coherence tomography (OCT) and adaptive optics to enable better diagnosis and monitoring of neuron-affecting diseases such as glaucoma. Traditional OCT is able to scan the thickness of retinal cell layers, but cannot visualize individual retinal ganglion cells. The new technique improves upon imaging by tracking changes in the number and shape of the eye's retinal ganglion cells. The axons of retinal ganglion cells form the optic nerve that relays visual information to the brain; it is also these axons that are damaged in neurodegenerative diseases such as glaucoma. With greater sensitivity of detecting changes to individual neurons conferred by adaptive optics, AO-OCT imaging can detect disease at earlier stages and monitor disease progression more rapidly. However, the higher resolution also generates a large amount of data that causes an image analysis bottleneck, which the research team solved with the addition of deep-learning algorithms, dubbed WeakGCSeg. As one of the researchers states, “Our experimental results showed that WeakGCSeg is actually superior to human experts, and it’s superior to other state-of-the-art networks that can process volumetric biomedical images.” A potential application of this technology is for use in clinical trials. Because the technique can detect disease at earlier stages and at shorter time spans, it can more precisely and more quickly monitor differences in a progressive disease that otherwise would take the death of hundreds or thousands of cells and months or years to manifest. The research team plans to expand their technique to the visualization of other cell types, such as photoreceptors, and other neurodegenerative diseases.

Interview with Two LCA Patients Treated with CRISPR
NPR  interviewed two patients with Leber congenital amaurosis (LCA) who participated in a landmark study using CRISPR gene editing. It was the first study to deliver CRISPR for gene editing inside the human body. Specifically, the two patients, Carlene Knight and Michael Kalberer, are affected by a version of LCA caused by a mutation in the CEP290 gene, affecting the photoreceptors of the eye. Both are legally blind with very limited tunnel vision centrally; Knight additionally has nystagmus. LCA was a suitable disease to test in vivo applications of CRISPR gene editing for two reasons: The retina is too fragile a tissue to remove, edit in vitro and then return to the eye. Furthermore, the healthy version of the gene is too large to use with viral vectors in traditional gene therapy. Instead, viral vectors, injected subretinally, were engineered to carry genetic instructions to manufacture the CRISPR gene-editor inside the retina. As a point of scientific interest, the news article also mentions safety precautions such as using the lowest number of viruses, beginning the clinical trials with older patients whose vision was already extensively damaged, and treating only one eye in each patient. At the same time, there was much consideration for the possibility that these patients would lose the little bit of vision they had remaining. The researchers have treated a total of four patients, and hope to add more with a wider age range. At this point in time, the effect of the treatment is yet to be seen. However, as Kalberer says, "But to even have the possibility — it's a gift."

Joint Synchronization of Vision and Hearing in the Brain
Physics tells us that light and sound travel at different speeds. Yet, visual and sound input from the same source arriving at our sense organs are then perceived as synchronous by the brain, even though they are processed at different speeds. The brain accounts for this difference through tricks such as temporal recalibration, altering our sense of time to synchronize the joint perception of sound and vision. This recalibration depends on brain signals constantly adapting to the environment to sample, order, and associate sensory inputs. Researchers in Canada used magnetoencephalography (MEG) to image the brain waves of volunteers asked to view short flashes of light paired with sounds with a variety of delays. The participants were then asked to report whether they thought both happened at the same time. The scientists found that the volunteers' perception of simultaneity in an audio-visual pair of stimuli was strongly affected by their perception of simultaneity in the preceding pair. For example, an audio-visual stimulus pair that was perceived as asynchronous might be followed by perceiving the next audio-visual stimulus pair as synchronous, even when it's not. The MEG signals revealed that such active temporal recalibration is the result of a unique interaction between fast and slow brain waves in auditory and visual regions of the brain, with the faster oscillations riding on top of slower fluctuations to create discrete and ordered time slots to register the order of sensory inputs. The relative delay between neural auditory and visual time slots, in turn, illustrates a dynamic process that constantly adapts to each participant’s recent exposure to audiovisual perception, resulting in judgments of perceived simultaneity. The neurophysiological mechanisms of temporal recalibration may be relevant in disorders that affect audio and other sensory perception, such as in autism and schizophrenia.

In Other News
(1) Improved color vision with psychedelic drug use
(2) Mantis shrimp vision inspires design of surgical camera
(3) Fossilized eye bones indicate this tiny dinosaur hunted at night (Related)