Scientists at Johns Hopkins University have discovered how humans develop acute central vision before birth, identifying a carefully timed interaction between a molecule derived from vitamin A and thyroid hormones in the retina. The discovery challenges a decades-old explanation of how key light-sensitive cells are formed and could guide future treatments for macular degeneration, glaucoma and other vision-damaging diseases.
The research, which was based on laboratory-grown retinal tissue, was published in the journal Proceedings of the National Academy of Sciences.
Lab-grown retinas reveal how clear vision is formed
“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, who led the research. “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.”
To investigate how the human eye develops, researchers used organoids, small clumps of tissue grown from fetal cells that closely mimic parts of the retina. After observing these lab-grown retinas for several months, the team identified the cellular events that shape the foveola, the small region in the center of the retina responsible for sharper vision.
The study focused on cone photoreceptors, the light-sensitive cells that provide daytime and color vision. These cells eventually become blue, green, or red cones, each of which responds to different wavelengths of light. Although the foveola makes up only a small portion of the retina, it is responsible for approximately half of all human visual perception. Unlike the rest of the retina, where all three types of cones are present, the foveola contains only red and green cones.
A surprising transformation of cone cells
Humans are characterized by having three different types of cones that together allow a wide range of color vision. How exactly this specialized pattern develops has been a mystery for decades. According to Johnston, scientists have had difficulty studying this process because common research animals, such as mice and fish, do not develop the same arrangement of photoreceptor cells.
The new findings suggest that the patterning of cones in the foveola is established by a coordinated sequence of events in the early stages of fetal development. During weeks 10 to 12, a small number of blue cones appear in the developing foveola. However, by week 14, those cells have transformed into red and green cones.
The researchers found that this happens through two separate mechanisms. First, retinoic acid, a molecule derived from vitamin A, is broken down, reducing the formation of new blue cones. Thyroid hormones then cause the remaining blue cones to become red and green cones.
“First, retinoic acid helps establish 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 there, you don’t see as well.”
Challenging a long-standing theory
The results offer a new explanation for a question that has baffled vision researchers for decades. The prevailing theory suggested that blue cones formed in the center of the retina and then migrated outward. Instead, new evidence indicates that those cells stay in place but change their identity to red and green cones, producing the specialized arrangement necessary for sharp vision.
“The main model in the field about 30 years ago was that somehow the few blue cones that are found in that region just move away, that these cells decide what they are going to be, and they remain this type of cell forever,” Johnston said. “We can’t really rule it out yet, but our data supports a different model. These cells actually convert over time, which is really surprising.”
Potential for restoration of future vision
Researchers believe these discoveries could eventually support new approaches to treating vision loss. Johnston’s team continues to improve their retinal organoids to more closely resemble the function of the human retina. Better models could help scientists produce healthier photoreceptor cells for future cell replacement therapies targeting diseases such as macular degeneration, which currently has no cure.
“The goal with using this organoid technology is to eventually create an almost made-to-order population of photoreceptors. A big potential avenue is cell replacement therapy to introduce healthy cells that can reintegrate into the eye and potentially restore that lost vision,” said Hussey, who is now a molecular and cellular biologist at cell therapy company CiRC Biosciences in Chicago. “These are very long-term experiments and of course we would need to optimize safety and efficacy studies before moving to the clinic. But it is a viable journey.”