Humans develop sharp vision during early embryonic development thanks to an interaction between a vitamin A derivative and thyroid hormones in the retina, Johns Hopkins University scientists have discovered.
The findings could overturn decades of conventional understanding of how the eye develops light-sensing cells and could inform new research into treatments for macular degeneration, glaucoma and other age-related vision disorders.
Details of the study, which used laboratory retinal tissue, are published today in Proceedings of the National Academy of Sciences.
“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 area and developing organoids that mimic its function, we hope to one day grow and transplant these tissues to restore vision.”
In recent years, the team has pioneered a new method for studying eye development using organoids, small clusters of tissue grown from embryonic cells. By monitoring these lab-grown retinas for several months, the researchers discovered the cellular mechanisms that shape the fovea—a central area of ​​the retina responsible for sharp vision.
Their research focused on light-sensitive cells that enable daytime vision. These cells develop into blue, green, or red cone cells that are sensitive to different types of light. Although the fovea comprises only a small portion of the retina, it accounts for approximately 50% of human visual perception. The foveola contains red and green cones but no blue cones, which are more widely distributed throughout the rest of the retina.
Humans are unique in having these three types of cones for color vision, allowing humans to see a wide range of colors that are relatively rare in other animals. How eyes grow with this cell distribution has puzzled scientists for decades. Mice, fish and other organisms commonly used for biological research lack this cell pattern, which makes photoreceptor cells difficult to study, Johnston said.
The Johns Hopkins team concluded that the distribution of cones in the fovea is the result of a coordinated process of cell fate determination and conversion during early development. Initially, a sparse number of blue cones are present in the fovea at weeks 10 to 12. But by week 14, they transform into red and green cones. The pattern occurs through two processes, the new study shows. First, a molecule derived from vitamin A called retinoic acid is broken down to limit the formation of blue cones. Second, thyroid hormones encourage the blue cones to turn into red and green cones.
First, retinoic acid helps to form the pattern. Thyroid hormone then plays a role in converting the remaining cells. That’s very important because if you have those blue cones in, you don’t see the same.”
Robert J. Johnston Jr., associate professor of biology, Johns Hopkins University
The findings offer a different perspective to the prevailing theory that blue cones migrate to other parts of the retina during development. Instead, the data suggest that these cells transduce to achieve an optimal distribution of cones in the fovea.
“The main model in the field about 30 years ago was that somehow the few blue cones you get in that area just go away, that those cells decide what they’re going to be and they stay that kind of cell forever,” Johnston said. “We can’t really rule it out yet, but our data supports a different model. These cells actually turn over time, which is really surprising.”
The findings could pave the way for new treatments for vision loss. Johnston and his team are working to refine their organoid models to better replicate the function of the human retina. These advances could lead to improved photoreceptors and possible cell therapies for eye diseases such as macular degeneration, which have no cure, said lead author Katarzyna Hussey, a former graduate doctoral student in the Johnston lab.
“The goal using this organoid technology is to eventually create a population of photoreceptors almost on demand. One major 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 cell biologist at the cell therapy company CiRC Biosciences at Chirc Biosciences. “These are very long-term experiments, and of course we’ll need to optimize for safety and efficacy studies before we move to the clinic. But it’s a viable journey.”
