Week in Review: Number 11

Genetic Insights to Rare Eye Disease MacTel
Macular telangiectasia type 2 (MacTel) is a rare eye disease that affects levels of amino acids in the eye, with both metabolic and genetic risk factors. MacTel affects roughly one in 5,000 people or two million people worldwide. An international study identified 22 gene variants that contribute to this degenerative macular disease. In particular, the research team found that variants of one gene encoding the rate-limiting serine biosynthetic enzyme phosphoglycerate dehydrogenase (PHGDH) were significantly associated with MacTel patients; the 22 variants of PHGDH together contribute to 3-4% of MacTel cases. While previous studies drew connections between MacTel and low levels of the amino acid serine, the discovery of the PHGDH gene was the long-sought missing link. Serine in turn is essential for the metabolic health and function of neurons in the eye and elsewhere in the body. Only one allele of the PHGDH gene needs to be affected to result in partial loss of enzyme function, leading to macular deterioration. Using human induced pluripotent stem cells, the researchers then confirmed that a PHGDH mutation leads to the production of toxic deoxysphingolipids (deoxySLs) previously shown to cause MacTel. Also of basic scientific interest is the genetic analysis of "groups of mutations" instead of individual mutations as in previous studies; the new analysis method was useful for identifying genes in small population sizes of people affected by rare diseases. These genetic studies provide valuable information toward better understanding and treatment of this rare eye disease.

Human Lacrimal Gland Organoids Grown In Vitro
Scientists in the Netherlands produced human lacrimal gland organoids in vitro that produced tears. The particular tear gland cell type they grew were ductal cells from adult human pluripotent stem cells. By using a modified cocktail of growth-stimulating factors, the researchers caused the tear cell organoids to produce lacrimal fluid, the hallmark of the lacrimal gland. Similar to the way people cry in response to pain, these tear gland organoids produce tears in response to the neurotransmitter norepinephrine/noradrenaline. The organoids shed tears in their lumen, not unexpected for ductal cells, and the amount of swelling could be used as an indicator of tear production. Additionally, the researchers explored the possibility of lacrimal gland transplantation. When transplanted into a mouse lacrimal gland, the human cells in these organoids integrated into the gland and formed duct structures. At two months, the cells were continuing to grow and divide and even produced tear proteins. Having a lacrimal gland model that responds to neurostransmitters to produce tears is useful in the study of diseases that affect the lacrimal glands, such as Sjogren's syndrome and cancers of the lacrimal gland, as well as facilitate an in vitro study of the effects of therapeutics.

Three-Dimensional Disadvantage
“We’re good at making technology, but sometimes we don’t really connect with it that well,” a senior author of the study comments, “And we don’t know that we don’t connect with it that well.” Researchers in the field of visual search recently conducted a study exploring how human vision processes 2D versus 3D images. The assumption in developing increasingly sophisticated imaging technologies is that detection success should increase with the additional information. However, this is not necessarily the case. The researchers found that we are actually worse at finding small targets in 3D image stacks than in single 2D images. According to the study, observers searching through 3D renderings had higher small target miss rates and significantly decreased decision confidence, though the observers also overestimated how much of the image they explored. Eye-tracking software, for example, showed that subjects conducting the 3D search were looking through only about half of the search area while reporting up to more than 80% image exploration.

This discrepancy lies in part in how we use central and peripheral vision. When searching through 2D images, observers tended to rely on their fovea, which offers the sharpest vision and is used for fixation, while they tended to rely on peripheral vision when searching through the composite images of 3D renderings, and move their eyes less. The combination of eye movement under-exploration, reliance on peripheral vision, and a bit of self-limiting search strategy on the part of radiologist participants in the study resulted in a high number of small target errors in 3D searches. The opposite was found for large targets, where detection improved in the 3D searches; this finding is consistent with use of peripheral vision. In illustrating the gaps between the availability of technology and how our eyes and brains process vision, the study is valuable in informing a better use of technology, for example, to use 2D images for small-target searches and 3D images for large-target searches. Additionally, implementing systems that don't possess these limitations, such as computer vision (e.g., deep learning neural networks), could improve detection success.

Retinal Scans for Early Detection of Childhood Autism
A scientist in Hong Kong is developing a method to use retinal scans for early detection of childhood autism. The technology uses a high-resolution retinal camera and artificial intelligence software to analyze retinal fiber layers and blood vessels to detect markers of autism. When tested on 70 children, 46 with autism and 24 without, the technology could identify those children with autism 95.7% of the time. The study size is small and it is not clear as to the severity of autism detected; nonetheless, the results are very encouraging. From a scientific standpoint, autism is added to the expanding list of neurological and systemic conditions that are detectable by eye exam. From a clinical standpoint, such a study is a big step toward bringing awareness to autism detection and intervention. As the researchers report, there is a stigma associated with mental illness, in this case with autism. That stigma might be higher in Asia. What is especially pertinent about this study is that it applies to children, whose parents could be in denial of the fact that their child needs treatment. An objective measure of biomarkers, in conjunction with professional assessment, could help to convince parents to enroll their children in therapy programs more quickly.

Dry Eye Disease Affects Health Beyond Vision
Dry eyes is a common multifactorial condition that affects millions of people, many of whom do not report their symptoms. Researchers in the U.K. conducted an online survey of 1000 people with dry eyes and compared them with 1000 people without the condition to explore how dry eyes affect quality of life. Unsurprisingly, they found that those with dry eye symptoms experienced worse quality of life. These effects extend beyond worse visual function and ocular discomfort to impact daily activities and work productivity for those with the most severe symptoms. The survey also revealed that those with dry eyes were also more likely to suffer anxiety and depression. The lead author of the study comments, “As well as confirming the impact on work and social lives we also discovered showed [sic] that the extent of the effects [is] consistent with the severity of symptoms. We also found that participants with dry eye disease symptoms were a lot more likely to suffer from other comorbidities...Whilst we cannot draw causal associations through this study, the presence of dry eye disease does appear to impact on an individual’s health and vision related quality of life.” Indeed a survey study design cannot untangle confounding factors that might underlie both dry eyes and systemic conditions, or naturally arise with age. However, interestingly, both groups in the study reported similar levels of screen time, though the group with dry eye symptoms also reported more exposure to environmental factors such as air conditioning, forced heating, or air pollution. Mitigating environmental factors could be helpful in addition to dry eye therapies.

In Other News
(1) Mammals share gene pathways that allow zebrafish to grow new eyes (Related)
(2) Beauty product expiration dates, including eye makeup
(3) Corneal transplants drive innovation: then and now