Science Daily

by Johns Hopkins University

    Scientists at Johns Hopkins University have uncovered a surprising role for a vitamin A derivative in the development of human vision. Their research reveals how this molecule works alongside thyroid hormones to help form the part of the eye responsible for our sharpest sight, challenging a scientific explanation that has stood for roughly 30 years.

    The discovery centers on an unexpected transformation that occurs in the developing retina before birth. Certain cells that initially detect blue light appear to change into cells sensitive to red and green light, helping create the specialized arrangement needed for clear central vision.

    Published in Proceedings of the National Academy of Sciences, the findings could reshape scientists' understanding of how human eyes develop. They may also help advance research into future treatments for macular degeneration, glaucoma, and other conditions that cause vision loss.

"This is a key step toward understanding the inner workings of the center of the retina, a critical part of the eye and the first to fail in people with macular degeneration," said Robert J. Johnston Jr., an associate professor of biology at Johns Hopkins University who led the study. "By better understanding this region and developing organoids that mimic its function, we hope to one day grow and transplant these tissues to restore vision."

How Scientists Recreated the Developing Human Retina

    To investigate how human vision forms, Johnston and his colleagues turned to an innovative laboratory technique they have helped develop over the past several years. Instead of relying entirely on animal experiments, they grew miniature versions of human retinal tissue called organoids.

    These small clusters of cells, grown from fetal cells, reproduce important features of developing human tissue. By observing the retinal organoids over several months, the scientists could follow changes that would otherwise be extremely difficult to study during pregnancy.

    Their attention focused on the foveola, a tiny region at the very center of the retina. The retina is the light-sensitive layer at the back of the eye that converts incoming light into signals the brain can interpret. Within it, the foveola plays an especially important role in detailed central vision, which allows people to read, recognize faces, and distinguish fine details.

    Although the foveola occupies only a small fraction of the retina, it is involved in approximately 50% of human visual perception, according to the researchers.

The Surprising Secret Behind Sharp Human Vision

    One of the keys to understanding the foveola is a group of specialized light-detecting cells called cones. Unlike rod cells, which are particularly important for seeing in dim light, cones support daytime vision and allow us to perceive color.

    Humans have three types of cone cells, each most sensitive to different wavelengths of light. These are commonly described as blue, green, and red cones. By comparing signals from these different cells, the brain can distinguish a remarkably broad range of colors.

    However, the cones are not distributed evenly throughout the retina. The foveola contains red and green cones but lacks blue cones, which are found in other retinal regions. This precise arrangement is essential for the exceptionally sharp vision produced by the center of the eye.

    For decades, researchers have struggled to explain how this pattern develops. One major obstacle is that commonly studied animals, including mice and fish, do not share the same retinal organization found in humans. That makes it difficult to use traditional animal models to investigate how these specialized cells develop.

    The laboratory-grown human retinas offered a new opportunity to solve this longstanding mystery.

Vitamin A and Thyroid Hormones Trigger a Remarkable Change

    The researchers discovered evidence that the arrangement of cones in the foveola develops through two coordinated processes. Together, they determine which types of cells form in the central retina and how some of those cells change as development continues.

    During weeks 10 through 12 of fetal development, a small number of blue cones are initially present in the foveola. By week 14, however, these cells appear to have transformed into red and green cones.

    The team identified two important chemical influences behind this process.

    The first involves retinoic acid, a molecule produced from vitamin A. Retinoic acid helps regulate how cells develop and specialize throughout the body. In the developing retina, the breakdown of this molecule limits the formation of blue cones in the central region.

    The second influence comes from thyroid hormones, which are best known for regulating metabolism but also have crucial roles in growth and development. In this case, the hormones appear to encourage the remaining blue cones to change into red and green cones.

"First, retinoic acid helps set the pattern. Then, thyroid hormone plays a role in converting the leftover cells," Johnston said. "That's very important because if you have those blue cones in there, you don't see as well."

    Importantly, the discovery concerns how vitamin A signaling helps guide eye development before birth. It does not establish that taking vitamin A supplements can improve sharp vision in adults.

A Discovery That Challenges a 30-Year-Old Theory

    The results offer a striking alternative to an explanation that has influenced vision research for decades.

    Under the longstanding model, blue cones that initially appear in the foveola were thought to move away as the retina developed. Scientists generally assumed that once these cells became a particular type of cone, their identities remained fixed.

    The new findings suggest something different. Rather than simply relocating, at least some blue cones may undergo a change in identity, becoming red or green cones as the eye develops.

"The main model in the field from about 30 years ago was that somehow the few blue cones you get in that region just move out of the way, that these cells decide what they're going to be, and they remain this type of cell forever," Johnston said. "We can't really rule that out yet, but our data supports a different model. These cells actually convert over time, which is really surprising."

    The researchers have not completely ruled out the possibility that some cells migrate. Nevertheless, their observations support the idea that developing cone cells have more flexibility than previously recognized.

    That possibility could fundamentally change how scientists study the formation of human color vision and the development of the retina's most specialized regions.

Could the Discovery Help Scientists Restore Lost Vision

    Beyond explaining how healthy eyes develop, the findings could have important implications for treating diseases that damage the retina.

    One particularly promising application involves macular degeneration, a major cause of central vision loss, especially among older adults. The disease damages the macula, the retinal region responsible for detailed central vision, and can severely interfere with reading, driving, and recognizing faces. Although treatments can slow or manage certain forms of the disease, there is currently no cure.

    Understanding how the retina creates its specialized light-sensitive cells could eventually help scientists produce healthy replacements in the laboratory.

    Johnston's team is now working to improve its retinal organoids so they more closely reproduce the structure and function of the human eye. The long-term goal is to develop precisely controlled populations of photoreceptors, the cells that detect light, for potential transplantation into damaged retinas.

    Katarzyna Hussey, a study author and former doctoral student in Johnston's laboratory, believes this approach could open an important new direction for vision restoration. Hussey is now a molecular and cell biologist at CiRC Biosciences, a cell therapy company in Chicago.

    "The goal with using this organoid tech is to eventually make an almost made-to-order population of photoreceptors. A big avenue of potential is cell replacement therapy to introduce healthy cells that can reintegrate into the eye and potentially restore that lost vision," said Hussey.

    The idea is to introduce healthy cells that could integrate with existing retinal tissue and potentially replace functions lost to disease. Achieving that goal would require researchers to demonstrate that transplanted cells can survive, connect properly with the eye's existing circuitry, and function safely.

    Hussey emphasized that the technology remains far from routine clinical use, with extensive development and testing still necessary.

"These are very long-term experiments, and of course we'd need to do optimizations for safety and efficacy studies prior to moving into the clinic. But it's a viable journey."

    For now, the discovery provides something fundamental: a clearer explanation of how the human eye develops its remarkable ability to see fine details. By revealing how vitamin A signaling and thyroid hormones help shape the retina, scientists have taken another step toward understanding vision at its earliest stages and potentially finding ways to restore it when disease strikes.