In a breakthrough study published in PLOS Biology, scientists grow human retinas in vitro to decipher the intricate genetic dance behind our ability to see millions of colors.
The research challenges long-held beliefs about the formation of red and green cone cells and provides insights into diseases like macular degeneration.
Led by biology associate professor Robert Johnston, the research not only deepens our comprehension of color blindness, age-related vision loss, and photoreceptor cell-related diseases but challenges previous assumptions about the role of thyroid hormones in the process.
“These retinal organoids allowed us,” remarks the professor, “for the first time to study this very human-specific trait. It’s a huge question about what makes us human, what makes us different.”
The results, which were published in PLOS Biology, contribute to a better understanding of color blindness, age-related visual loss, and other disorders associated with photoreceptor cells.
They also demonstrate how genes teach the human retina to produce certain color-sensing cells, a process previously believed to be regulated by thyroid hormones.
By manipulating the cellular properties of the organoids, the team found retinoic acid as the crucial determinant of whether a cone specializes in sensing red or green light, a feature exclusive to humans and closely related primates.
For decades, scientists assumed that red cones produced by a coin toss mechanism in which cells indiscriminately commit to perceiving green or red wavelengths—but Johnston’s team recently suggested that the process may be regulated by thyroid hormone levels. Instead, the new study implies that red cones form as a result of a precise series of events choreographed by retinoic acid inside the retina.
“There still might be some randomness to it, but our big finding is that you make retinoic acid early in development,” Johnston adds. “This timing really matters for learning and understanding how these cone cells are made.”
Except for a protein called opsin, which detects light and informs the brain what colors humans perceive, green and red cone cells are strikingly identical. Different opsins govern whether a cone becomes a green or red sensor, despite the fact that the genes for each sensor are 96% identical. They followed cone ratio changes over 200 days using a novel approach that detected those small genetic alterations in the organoids.
“Because we can control in organoids the population of green and red cells, we can kind of push the pool to be more green or more red,” explains author Sarah Hadyniak. “That has implications for figuring out exactly how retinoic acid is acting on genes.”
The team also mapped the vastly variable ratios of these cells in 700 adult retinas. One of the most interesting discoveries of the new study, according to Hadyniak, was seeing how the proportions of green and red cones altered in individuals.
Scientists are still puzzled as to how the ratio of green and red cones can shift so much without changing vision. If these cells controlled the length of a human arm, the varying ratios would result in “amazingly different” arm lengths, according to Johnston.
The researchers are collaborating with other Johns Hopkins laboratories to get a better understanding of disorders such as macular degeneration, which involves the loss of light-sensing cells near the center of the retina. The objective is to have a better understanding of how cones and other cells communicate with the nervous system.
“The future hope is to help people with these vision problems,” Johnston says. “It’s going to be a little while before that happens, but just knowing that we can make these different cell types is very, very promising.”
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