Week in Review: Number 19

Optogenetics & Vision: Interview with José-Alain Sahel
Review of Optology earlier highlighted media coverage of a breakthrough story of the first clinical application of optogenetics to restore partial vision to a patient with terminal retinitis pigmentosa. An interview with the lead author of the study, José-Alain Sahel, in CNRS News  published this week takes a closer look at the research behind the scenes. Originally developed to study neural circuits of the brain, Sahel explains that a colleague's work applying the technique to the circuits of the retina prompted the idea to apply optogenetics to visual impairment. "This project required a lot of time and a great deal of tenacity," he revealed, "Although some of our colleagues thought this project was ludicrous, we held our course because we knew it made sense."

The challenges the team faced over the twelve years of the project included choosing the right proteins for the right type of cell, determining how they could be stimulated effectively, and developing visual rehabilitation protocols for patients. The researchers first explored injecting the proteins in bipolar cells, then in dormant photoreceptors. Though the latter experiments were successful at reactivating dormant cones, the proteins could not be sufficiently strongly expressed in these cells; work continues to be done in this area. They next turned their attention to retinal ganglion cells, which naturally react to light with melanopsin. Responsible for regulating circadian rhythm, melanopsin nonetheless responds too slowly for a strategy to stimulate vision. Sahel's team tested green fluorescent proteins before colleagues suggested channelrhodopsin (CrimsonR), which responds to low-energy amber light that they were looking for. The next obstacle was creating a projection system to stimulate the CrimsonR proteins. Because the application is rather unique, they set up a company, GenSight Biologics, to develop both the gene therapy and the equipment for its application. Finally, they collaborated with a platform called StreetLab to train the patients to use the light-stimulating goggles in real-life conditions. Sahel adds, "Our research is carried out in close collaboration with the patients, who play an active role in our work. We are convinced that in terms of rehabilitation, close ties between actors, developers and users are essential."

Reducing Light Exposure and Neuronal Activity Decreases Risk of Optic Glioma, in Mice
Seeing, hearing, thinking all require brain activity. But for those at risk, the normal day-to-day activity of neurons can drive the formation and growth of brain tumors, such as optic gliomas in this case. Since the neurons of the optic nerve become active when exposed to light, the researchers wanted to investigate whether reducing exposure to light could decrease neuronal activity and thereby limit tumor formation. Using a mouse model of neurofibromatosis type 1 (NF1), they found that mice with Nf1 mutations raised under normal lighting developed tumors, while those kept in the dark during a critical period of development did not. Additional experiments narrowed down the critical window to age 6 to 12 weeks in these mice. None of the mice reared in the dark during that time frame developed tumors by 24 weeks of age. Limited effect was seen beyond the critical window; when the tumors have already formed, placing the mice into darkness slowed tumor growth but did not shrink them. In both mice with Nf1 mutations and in tissue samples of people with low-grade brain tumors, tumor formation was associated with abnormally high levels of a protein called neuroligin 3. In mouse studies, blocking the protein with a drug or eliminating the protein through genetic modification resulted in fewer and smaller tumors. Understanding risk factors for tumor formation can help guide preventative strategies. As one of the senior authors states, “[N]ow that we know these brain tumors are caused by exposure to light and neuronal activity, we can start thinking of next-gen prevention strategies. Maybe we can give kids cool sunglasses to wear with filters or lenses to block out certain wavelengths of light, or repurpose drugs that suppress excessive neuronal activity, and protect these kids from developing brain tumors and losing their sight.”

Larger Pupils are Correlated with Higher Fluid Intelligence and Attention Control
New research finds a possible link between baseline pupil size and individual difference in cognitive ability. Beyond reacting to light intensity, pupils also indicate arousal, interest, and mental effort. Curious about the connection between pupil dilations as an indicator of mental effort, the researchers wanted to investigate whether pupil size was also a measure of intelligence. The study involved 500 participants aged 18 to 35, whose pupils were measured with an eye tracker while they stared at a blank computer screen for up to four minutes. These participants then performed tests in fluid intelligence (the capacity to reason through new problems), working memory capacity (the ability to remember information over a period of time), and attention control (the ability to focus attention amid distractions and interference). After controlling for age-related decreases in pupil size, the researchers found that larger baseline pupil size was correlated with better performance in fluid intelligence and attention control and, to a lesser degree, working memory capacity in all but the brightest lighting conditions. They hypothesize that people with larger pupils at rest have greater regulation of activity by the locus coeruleus, a nucleus situated in the upper brain stem that is responsible for releasing norepinephrine as well as regulating a range of neural processes such as perception, attention, learning and memory. Though more research is needed to determine why larger pupils are correlated with higher fluid intelligence and attention control, studies such as this provide a better glimpse through that proverbial "window of the soul."

Screen Time, Sleep Quality, and Myopia
Research led by an optometrist in Australia investigated the link between sleep quality and myopia. The findings indicate that people with near-sightedness have lower production of melatonin and more delayed circadian rhythms, compared to those with normal vision. The study involved a small cohort—18 myopes and 14 emmetropes—of university students, with endogenous melatonin levels measured through saliva and urine samples. The differences in sleep patterns in myopes compared to emmetropes include being more likely to go to bed later (i.e., be "night owls"), taking longer to fall asleep, and sleeping for shorter periods of time. Other research in the field suggest a link between excessive screen use and the onset of the condition in young children, with cases of myopia on the rise globally. As the researcher says, "A lot of digital devices emit blue light, which can suppress the production of melatonin and cause delay in circadian rhythms at night, resulting in delayed and poor sleep...Adequate sleep is critical for learning, memory, sustained attention, academic performance at school, and general wellbeing of children during the early development...It is important to limit the exposure to digital devices in children, particularly at night, for ensuring good sleep and healthy vision." He next plans to study light exposure at night, melatonin production, and circadian rhythms during childhood, when risk of developing myopia is highest.

Screen Time and Myopia During COVID-19
An article in the Wall Street Journal  summarizes key points about the link between myopia and increased screen time during the COVID-19 pandemic, as reported by several ophthalmologists. One theory suggests that when children engage in prolonged near work, such as on screens or reading books, the eye becomes used to near focus, which may cause lengthening of the eyeball, leading to myopia. Less time spent outdoors also contributes to the growing rates of myopia, as time spent outdoors often accompanies looking farther away (rather than near). Finally, the natural lighting of outdoor environments could also play a role in preventing myopia. The article touches upon an often cited study published in JAMA Ophthalmology  reporting overall increased rates of myopia among more than 120,000 homebound children in China. Doctors in the U.S. are seeing similar trends in their clinics, including trends toward high myopia (that is, myopia greater than six diopters), which puts these kids at increased risk of vision-threatening eye problems such as myopic degeneration and retinal detachment later in life. Alongside myopia, doctors also report more cases of digital eye strain during the pandemic, with symptoms including blurry vision, headaches and eye fatigue. One of the ophthalmologists interviewed has conducted a small survey during the first five months of this year among 110 children, ages 10 to 17, who had virtual schooling ranging from 3 to 10 hours. The data is preliminary and yet to be published, though the article reports that symptoms found include "eye aches, headaches, words moving around a page, blurry and double vision, and losing their place when they read, tearing and burning, rubbing eyes more often, dryness, and the sensation of a foreign body in the eye." Lastly, the pandemic has caused more complaints of dry eyes, especially among adults and associated with mask-wearing and reduced blink rate from screen use.

In Other News:
(1) The use of optogenetics in neuroscience
(2) Controlling brain states with rays of light
(3) J&J develops reshaping contact lenses for childhood myopia