Week in Review: Number 45

Interview: From Neurons to Artificial Visual Systems, with a Dash of Inspired Science Outreach
The brain's visual system is central to our perception and interpretation of the world we see. Yet, how it gathers and integrates visual information into a cohesive whole still remains largely a mystery. Harvard Medicine News  interviewed Carlos Ponce, M.D., Ph.D., assistant professor of neurobiology at HMS, about his interest in the visual system and how he uses this information to build better computational models. Ponce explains that his research is focused on the brain's ventral stream, or parts of the visual system that analyze and categorize shapes, whether they be faces, objects, scenes, etc. He uses macaque monkeys as animal models, since they are an experimental model with brains most similar to humans. Using images as stimuli and electrophysiology recordings, Ponce studies how the responses of neurons approximate our visual perception. As he explains, "The pictures represent a hypothesis, and the neural response is an evaluation of that." However, images that are selected by human minds cannot fully capture the range of variability and nuance in visual stimuli that the brain encounters in the world; the images we select as input are limited by our imaginations and biases. This is where advances in computational modeling come in handy. The models not only learn from the input of millions of pictures, but can also generate entirely new images.

In an earlier paper from 2019, Ponce presents how applying this "cooperation between neurons and machine intelligence" to neurons in part of the macaque brain that responds to faces produced, from initial noise, a computational model that contained features of a face. "Our discovery was that you can couple computational models to neurons in the macaque brain that are visually responsive, and have the neurons guide the model to create pictures that activate them best," the assistant professor explains, "However, we were puzzled by some of the pictures that were created. Some made a lot of sense, like parts of faces or bodies, but others didn’t look like any one object. Instead, they were patterns that cut across semantic categories...We realized that the neurons in the macaque brain are learning specific motifs that don’t necessarily fit our language. The neurons have a language of their own that is about describing the statistics of the natural world." In a sequel of the research, published this year, Ponce applied computational models to both the posterior (upstream) parts of the macaque brain that process simple objects and the more anterior (downstream) parts that process complex shapes. In doing so, he was able to quantify the information coming from the neurons as having an intermediate level of complexity, somewhere between the simplicity of a line and the complexity of a photograph. In other experiments, he found that macaques prefer to look at parts of pictures that were similar to the features encoded by their neurons. "That gives us a clue that during development, the brain extracts important patterns from the world and stores those patterns in neurons," he says.

When asked what he wants to do next, Ponce answers that he is intrigued by many questions, such as extending his individual-neuron recordings to characterize full populations of neurons, or reconstructing images of what the brain sees based on the pattern of activity of neurons. He is also interested in how clusters of neurons that share a function develop where they do in the brain, and hopes that his approach will help to map that topography. Once we are able to characterize the patterns and networks of the brain, he states, we can then develop computational models to improve artificial visual systems. Ponce recalls his own medical training to connect his research to clinical applications, for example, to save lives through improved screening that "doesn't miss anything." Finally, he references his own childhood and inspiration from scientists to motivate his work in science outreach to youth, to inspire young students every year toward careers in science.

Large Association Study Finds Cataract Surgery Linked with Lower Risk of Dementia
Cataracts are an opacification or clouding of the eye's crystalline lens, most commonly as a result of aging and decades of filtering ultraviolet radiation. Although connections between poor vision and cognitive decline have been explored in many studies, ophthalmologists at University of Washington were interested in the effect of surgical intervention in the form of cataract extraction on dementia risk. Specifically, they looked at data from the Adult Changes in Thought (ACT) study, an ongoing longitudinal cohort study started in 1994 by Kaiser Permanente Washington and designed to study the development of dementia. Electronic medical records data was collected from 3,038 participants 65 years of age or older who had either cataract or glaucoma diagnosis before enrollment or during follow-up care. Among those included in the analysis, there were 853 cases of dementia (all cause) and 709 cases of Alzheimer's disease. Approximately half of the participants (1,382 individuals) had cataract surgery. Based on 23,554 person-years of follow-up, and after controlling for a variety of potentially confounding factors, participants who underwent cataract extraction in either eye had a 29% reduced risk of developing dementia compared to participants without surgery; moreover, the reduced risk applied for at least 10 years after surgery. Similar findings were seen in dementia specific to Alzheimer's disease. Importantly, no association was observed between glaucoma surgery and dementia risk. The authors point out that evaluation of glaucoma surgery, which, unlike cataract surgery, does not restore vision, was to address potential healthy patient bias. Although the mechanisms by which cataract extraction is associated with decreased dementia risk were not explored in this observational study, the researchers hypothesize that patients were getting higher quality sensory input after cataract extraction, highlighting neurological, circadian, and social improvements. Lead researcher of the study states, "This kind of evidence is as good as it gets in epidemiology. This is really exciting because no other medical intervention has shown such a strong association with lessening dementia risk in older individuals." Given the risk of cognitive decline in older age, interventions such as cataract surgery have major clinical relevance not only in enhancing quality of vision but also in improvement of mental health.

Large Single-Cell Gene Atlas of Human Eye Disorders
An international team led by researchers from several universities in Singapore, with colleagues in the U.S. and other countries, have produced the first single-cell atlas of human and porcine eyes. They report applying single-cell RNA sequencing to catalogue more than 50,000 cells in human and porcine eyes, as well as developing a cell atlas that distinguishes these cells by the activity of their genes. The use of porcine eyes (and other animal species, such as zebrafish) in this study allowed for comparison of interspecies differences as well as conserved regulating factors in the eye, which the authors state is lacking in integrative research of the eye. The study produced a wide range of findings, some of which are simple, such as evidence of adult stems cells in iris tissue. Others have clinical implications regarding ocular routes of infection and disease transmission. For example, the team found that ACE2 and TMPRSS2, the primary cell surface proteins responsible for entry of SARS-CoV-2 into human, are expressed in the eye's conjunctival cells. Some of the researchers also worked on lab techniques in regenerative medicine, such as using embryonic stem cells to generate retinal ganglion cell (RGC) progenitors in culture; they discovered that a switch called KLF7 could accelerate RGC generation, with results that could inform potential therapies for eye diseases like glaucoma that results from progressive damage to the RGCs that make up the optic nerve. They are working to further validate the KLF7-derived RGCs for preclinical studies, with broad aims of understanding key molecular switches to better engineer lab-grown cells as a means of therapy.

i27-Breg: Discovery of a New Anti-inflammatory B Cell
Scientists at the National Eye Institute have discovered a new type of B cell that tempers the immune system, thereby reducing chronic inflammation in autoimmune diseases. Termed regulatory B cells (Bregs), these cells represent a small population of B cells that are derived from plasma blasts or plasma cells; although similar to other Bregs, the newly discovered cells express a distinct genetic profile of innate B-1a cell lineage. Bregs patrol the blood and function in modulating the immune system through expression of anti-inflammatory cytokines (e.g., IL-10 and IL-35) that counterbalance the physiological effects of pro-inflammatory cytokines (e.g., IFN-gamma and IL-17). A balance between pro- and anti-inflammatory cytokines is essential to a healthy immune system, one that can mount a robust response against pathogens while not reacting excessively to self-cells, as in autoimmune disease. In lab tests in mice, purified infusion of i27-Breg suppressed autoimmune uveitis (and encephalomyelitis) through "up-regulation of inhibitory receptors (Lag3, PD-1), suppression of T-cell (Th17/Th1) responses, and propagation of inhibitory signals that converted conventional B cells to regulatory lymphocytes that secrete IL-10 and/or IL-35 in eye, brain, and spinal cord." Unlike i35-Breg, a similar Breg also discovered by these researchers, i27-Breg demonstrated a quicker response to suppress autoimmune uveitis and MS-like disease. i27-Breg also has an advantage of being able to proliferate to sustain IL-27 secretion in vivo, suggesting that it may have greater therapeutic potential over biologics (IL-10 or IL-35), which are rapidly cleared by the body. Notably, IL-27 receptor is necessary for any therapeutic effect, as i27-Breg infusions into mice lacking the IL-27 receptor failed to attenuate disease symptoms. Finally, because i27-Breg is neither antigen-specific nor disease-specific, the researchers point out that it could be effective immunotherapy for a wide range of autoimmune diseases. They are currently working on the use of exosomes (extracellular vesicles) as a vector to deliver lab-grown IL-27 into the body, which they acknowledge is less technically challenging than producing Breg cells in the lab.

Suprachoroidal Bionic Eye Implant Trialled in Sheep
Researchers in Australia are investigating a new type of bionic eye implant for the treatment of degenerative retinal diseases. The result of "decades of experience and technological breakthroughs in the field of implantable electronics," the Phoenix⁹⁹  Bionic Eye is a 98-channel visual prosthesis comprising two components: a stimulator implanted in the eye in the suprachoroidal space and a communication module positioned under the skin behind the ear. This system is attached to an external glasses-mounted miniature camera that captures images to send instructions wirelessly to the communication module behind the ear, which decodes and transfers the signals to the stimulation module behind the retina. The research team has tested implantation of 9 devices in an ovine (sheep) model, reporting positive results up to 3 months in this study. One of the engineers on the project remarks, "Importantly, we found the device has a very low impact on the neurons required to ‘trick’ the brain. There were no unexpected reactions from the tissue around the device and we expect it could safely remain in place for many years." Implant stability and safety profile were assessed with indirect ophthalmoscopy, infrared imaging, and optical coherence tomography. Biocompatibility was evaluated with histological analysis with an emphasis on the health of the retinal cells; only mild fibrosis and inflammation of the surrounding tissue were observed. Although assessments of visual function were not conducted, the researchers state being confident with the results in terms of safety to submit ethics approval for human clinical trials. They continue to make refinements in more advanced stimulation and surgical techniques in the meantime.

In Other News
(1) New contrast sensitivity test created by NECO faculty
(2) The human visual system's awesome complexity: Are we ready for self-driving cars?
(3) Dark adaptometry device for screening of Plaquenil retinal toxicity