Scientists at Johns Hopkins University have discovered the surprising role of a vitamin A derivative in the development of human vision. Their research reveals how this molecule works alongside thyroid hormones to form the part of the eye responsible for our sharpest vision, calling into question a scientific explanation that has been around for around 30 years.
The discovery centers on an unexpected transformation that occurs in the developing retina before birth. Some cells that initially detect blue light appear to transform into cells sensitive to red and green light, helping to create the specialized arrangement necessary for clear central vision.
Published in Proceedings of the National Academy of Sciencesthe findings could reshape scientists’ understanding of human eye development. They could also help advance research into future treatments for macular degeneration, glaucoma and other conditions leading to 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 study how human vision is formed, Johnston and his colleagues turned to an innovative laboratory technique that they helped develop over the past several years. Instead of relying entirely on animal experiments, they developed miniature versions of human retinal tissue called organoids.
These small clusters of cells, derived from fetal cells, reproduce important characteristics of human tissue development. By observing retinal organoids over several months, scientists were able to track changes that would otherwise be extremely difficult to study during pregnancy.
Their attention focused on the foveola, a small region located 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 that the brain can interpret. Within this, the foveola plays a particularly 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 about 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 colors.
Humans have three types of cone cells, each of which is most sensitive to different wavelengths of light. These are commonly described as blue, green and red cones. By comparing the signals emitted by these different cells, the brain can distinguish a remarkably wide range of colors.
However, the cones are not evenly distributed throughout the retina. The foveola contains red and green cones but lacks blue cones, which are found in other regions of the retina. This precise arrangement is essential to the exceptionally sharp vision produced by the center of the eye.
For decades, researchers have struggled to explain how this trend develops. A major obstacle is that commonly studied animals, including mice and fish, do not share the same retinal organization found in humans. This makes it difficult to use traditional animal models to study the development of these specialized cells.
Laboratory-grown human retinas have offered a new opportunity to solve this long-standing mystery.
Vitamin A and thyroid hormones trigger remarkable change
The researchers found evidence that the arrangement of cones in the foveola develops through two coordinated processes. Together, they determine what types of cells form in the central retina and how some of these cells change as development continues.
During weeks 10 to 12 of fetal development, a small number of blue cones are initially present in the foveola. However, by week 14, 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 the development and specialization of cells throughout the body. In the developing retina, the degradation 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 play a crucial role in growth and development. In this case, hormones seem to encourage the remaining blue cones to turn into red and green cones.
“First, retinoic acid helps set the pattern. Second, thyroid hormone plays a role in converting the remaining cells,” Johnston said. “It’s very important because if you have these blue cones in there, you don’t see as well.”
Importantly, this finding relates to how vitamin A signaling helps guide eye development before birth. It does not establish that taking vitamin A supplements can improve vision in adults.
A discovery that calls into question a 30-year-old theory
The findings offer a striking alternative to an explanation that has influenced vision research for decades.
According to the long-standing model, the blue cones that initially appear in the foveola were thought to move further apart as the retina developed. Scientists generally thought that once these cells became a particular type of cone, their identity remained fixed.
The new findings suggest something different. Rather than simply moving, 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 about 30 years ago was that somehow the few blue cones that you find in that region move out of the way, those cells decide what they’re going to be, and they stay that type of cell forever,” Johnston said. “We can’t really rule that out yet, but our data supports a different model. These cells convert over time, which is really surprising.”
The researchers do not completely rule out the possibility that some cells migrate. Nonetheless, their observations support the idea that developing cone cells have more flexibility than previously thought.
This possibility could fundamentally change the way scientists study the formation of human color vision and the development of the most specialized regions of the retina.
Could the discovery help scientists restore lost vision?
Beyond explaining how healthy eyes develop, these findings could have important implications in treating diseases that damage the retina.
One particularly promising application concerns macular degeneration, a major cause of central vision loss, particularly among older adults. The disease damages the macula, the retinal region responsible for detailed central vision, and can seriously interfere with reading, driving and recognizing faces. Although treatments can slow or manage some 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 replacement cells in the laboratory.
Johnston’s team is currently working to improve their retinal organoids so that they more closely replicate 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 possible transplantation into damaged retinas.
Katarzyna Hussey, study author and former doctoral student in Johnston’s lab, believes this approach could open an important new direction for vision restoration. Hussey is now a molecular and cellular biologist at CiRC Biosciences, a cell therapy company in Chicago.
“The goal of using this organoid technology is to ultimately create an almost tailor-made population of photoreceptors. A big potential avenue is cell replacement therapy to introduce healthy cells that can integrate back into the eye and potentially restore that lost vision,” Hussey said.
The idea is to introduce healthy cells that could integrate into existing retinal tissue and potentially replace functions lost to disease. To achieve this goal, researchers would need to demonstrate that the transplanted cells can survive, connect properly to the eye’s existing circuits, and function safely.
Hussey emphasized that the technology remains far from routine clinical use, and that extensive development and testing is still needed.
“These are very long-term experiments, and of course we will have to make optimizations for safety and effectiveness studies before moving to the clinic. But it is a viable journey.”
For now, the discovery provides something fundamental: a clearer explanation of how the human eye develops its remarkable ability to see the smallest details. By revealing how vitamin A signaling and thyroid hormones help shape the retina, scientists have taken another step toward understanding vision in its earliest stages and potentially finding ways to restore it when disease strikes.
Gn Health
