Scientists at Johns Hopkins University have uncovered how humans develop sharp central vision before birth, identifying a carefully timed interaction between a vitamin A derived molecule and thyroid hormones in the retina. The discovery challenges a decades old explanation for how key light sensing cells form and could guide future treatments for macular degeneration, glaucoma, and other diseases that damage vision.
The research, which relied on lab grown retinal tissue, was published in the Proceedings of the National Academy of Sciences.
Lab Grown Retinas Reveal How Sharp Vision Forms
“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, the researchers used organoids, small clusters of tissue grown from fetal cells that closely mimic parts of the retina. After observing these lab grown retinas over several months, the team identified the cellular events that shape the foveola, the tiny region at the center of the retina responsible for the sharpest vision.
The study focused on cone photoreceptors, the light sensing cells that provide daytime and color vision. These cells eventually become blue, green, or red cones, each responding to different wavelengths of light. Although the foveola makes up only a small portion of the retina, it is responsible for about half of all human visual perception. Unlike the rest of the retina, where all three cone types are present, the foveola contains only red and green cones.
A Surprising Transformation of Cone Cells
Humans are unusual in having three different cone types that together allow a broad range of color vision. Exactly how this specialized pattern develops has remained a mystery for decades. According to Johnston, scientists have struggled to study 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 cone pattern in the foveola is established through a coordinated sequence of events early in fetal development. During weeks 10 through 12, a small number of blue cones appear in the developing foveola. By week 14, however, those cells have changed 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. Then thyroid hormones drive the remaining blue cones to convert 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.”
Challenging a Longstanding Theory
The results offer a new explanation for a question that has puzzled vision researchers for decades. The prevailing theory suggested that blue cones formed in the center of the retina and later migrated outward. Instead, the new evidence indicates those cells remain in place but change their identity into red and green cones, producing the specialized arrangement needed for sharp vision.
“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.”
Potential for Future Vision Restoration
The researchers believe these discoveries could eventually support new approaches to treating vision loss. Johnston’s team is continuing to improve its retinal organoids so they 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 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, who is now a molecular and cell biologist at cell therapy company CiRC Biosciences in Chicago. “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.”