Lab-grown retinas explain why people see colors dogs can’t see

With human retinas grown in a petri dish, researchers discovered how a derivation of vitamin A generates specialized cells that allow humans to see millions of colors, an ability that dogs, cats and other mammals only possess. not.

“These retinal organoids allowed us for the first time to study this very human-specific trait,” said author Robert Johnston, associate professor of biology. “It’s a huge question of what makes us human, what makes us different.”

The results, published in PLOS Biology, improve understanding of color blindness, age-related vision loss, and other diseases related to photoreceptor cells. They also demonstrate how genes direct the human retina to make specific color-detecting cells, a process that scientists thought was controlled by thyroid hormones.

By changing the cellular properties of the organoids, the research team discovered that a molecule called retinoic acid determines whether a cone will specialize in detecting red or green light. Only humans with normal vision and closely related primates develop the red sensor.

For decades, scientists thought that red cones formed through a coin-flip mechanism in which cells randomly committed to detecting green or red wavelengths. Research by Johnston’s team recently suggested that the process may be controlled by thyroid hormone levels. Instead, the new research suggests that red cones materialize through a specific sequence of events orchestrated by retinoic acid in the eye.

The team found that high levels of retinoic acid early in organoid development correlated with higher ratios of green cones. Similarly, low levels of acid changed the genetic instructions of the retina and generated red cones later in development.

“There may still be some element of chance involved in this, but our big discovery is that retinoic acid is produced early in development,” Johnston said. “This timing is really important for learning and understanding how these cone cells are made.”

Green and red cone cells are remarkably similar, except for a protein called opsin, which detects light and tells the brain what colors people see. Different opsins determine whether a cone will become a green or red sensor, although the genes for each sensor remain 96% identical. Using a revolutionary technique that spotted these subtle genetic differences in the organoids, the team tracked changes in the cone ratio over 200 days.

“Because we can control in organoids the population of green and red blood cells, we can sort of nudge the pool to be greener or redder,” said author Sarah Hadyniak, who led the research as student in Johnston’s lab and is now at Duke University. “This has implications for determining exactly how retinoic acid acts on genes.”

The researchers also mapped the highly variable proportions of these cells in the retinas of 700 adults. Seeing how the proportions of green and red cones changed in humans was one of the most surprising findings of the new research, Hadyniak said.

Scientists still don’t really understand how the ratio of green to red cones can vary so much without affecting a person’s vision. If these cell types determined the length of a human arm, the different ratios would produce “surprisingly different” arm lengths, Johnston said.

To better understand diseases such as macular degeneration, which causes the loss of light-sensitive cells near the center of the retina, researchers are working with other Johns Hopkins laboratories. The goal is to deepen their understanding of how cones and other cells link to the nervous system.

“The hope for the future is to help people with these vision problems,” Johnston said. “It’s going to take a little while for that to happen, but just knowing that we can make these different types of cells is very, very promising.”

Other Johns Hopkins authors include Kiara C. Eldred, Boris Brenerman, Katarzyna A. Hussey, Joanna FD Hagen, Rajiv C. McCoy, Michael EG Sauria, and James Taylor; as well as James A. Kuchenbecker, Thomas Reh, Ian Glass, Maureen Neitz and Jay Neitz of the University of Washington.