Dreaming in Color
Kiara Eldred studies how retinal cells develop
The retina of the eye has two kinds of photoreceptors that allow us to see: rods and cones. While rods work at low levels of light and let us see in the dark, cones allow us to see in the daytime and to perceive color. Cone cells use a photosensitive protein called opsin that allows them to respond to specific colors. We have three different types of cones, each with a different type of opsin: red, green, or blue.
At Johns Hopkins, sixth-year Ph.D. student Kiara Eldred is studying how cone cells develop, and what biological cues are required for them to form. Previous research from mouse and zebrafish studies had showed that a specific hormone, thyroid hormone, plays a large part in determining which cone cells become which color, but Eldred needed to test it on human cells.
Since retinal cells form during fetal development, this wasn’t something easily viewed. Eldred had to figure out how to grow human stem cells into retinal tissue—a creation called an organoid.
That’s when she and her faculty advisor, Bob Johnston, Ph.D., turned to the Co-Director of Johns Hopkins Center for Stem Cells and Ocular Regenerative Medicine (STORM) Donald Zack, M.D., Ph.D, , and his former postdoc, Karl Wahlin.
“I am so thankful for Karl, Don Zack, and the time they spent training me how to grow organoids,” Eldred says. “This is a really awesome thing about Hopkins: People are very collaborative here. I have been struck by how inviting everyone is and how open about their science they are.”
Once Eldred could grow those organoids, she could then test if thyroid hormone was important for making blue versus red or green cones. She found that if she eliminated one of the key receptors for the thyroid hormone in the retina, thyroid hormone receptor beta, only blue cones developed: not red or green. She then added thyroid hormone to the retinas, and saw the opposite; only red and green cones were created.This was an exiting discovery, allowing the lab to understand how those different cell types developed.
But she also wanted to know how thyroid hormone was regulated in the developing retina to produce the right proportions of the three cone types. Her research showed that blue cones are generated first, with red and green cones developing later. When she looked closely at the timing of expression of enzymes that regulate thyroid hormone levels in the retina, her findings indicated that the developing retinal tissue was controlling the levels of thyroid hormone. She saw that early there was low thyroid signaling to specify blue cones, and at later time points there was high thyroid signaling to produce red and green cones.
“What we found is that the retinal tissue itself is able to regulate levels of thyroid hormone. When these cells are born, they are directed to one cone fate or another. At early stages, low levels of hormone produce blue cones. As the retina creates more active hormone, red and green cones are then formed,” she says.
This correlates with several epidemiological studies evaluating vision in premature infants: They have a higher incidence of color vision deficiencies. When a woman is pregnant, her thyroid hormone levels are very high, so when a baby is born early, it’s removed from that high-thyroid signaling environment.
“We’re not suggesting a direct treatment, but instead a mechanism for why these premature infants may have these color defects,” she adds.
The short-term goals of Eldred’s work are to ask very basic questions about how we generate different cells, she explains. The long-term implications can be as far-reaching as the ability to build different parts of the retina for transplant.
The center of the retina houses our high-acuity vision, says Eldred. Only red and green cones are in that area; the blue cones are present as you move toward its periphery. Developing an understanding of how to make different regions of the retina that have different populations of cone cells can lead to the future development of effective retinal replacement tissue.
The more immediate plans stemming from this research are to collaborate with other scientists at Hopkins to implant the retinal cell tissue into animal models, and see if it can be used to integrate and restore sight, Eldred says. This could benefit people who are colorblind, but the more urgent wish is to help people who have lost portions of their sight, especially those affected by macular degeneration.
“The macula is located in the center region of the eye, where the densest amount of cones and the and highest number of red and green cones are located. So we are very interested in being able to make correct proportions to replace these specific regions of the eye,” she says.
At Hopkins, she recently defended her thesis and published her discovery as a first author in Science.
Under the umbrella
When Eldred first applied to graduate schools, she says, she wasn’t sure what she wanted to work on. She knew she wanted to study human biological problems, but wasn’t sure of the specifics. That’s why she appreciated Hopkins’ umbrella program, Cell, Molecular, Developmental Biology and Biophysics (CMDB), which provides access to a lot of different kinds of science.
“As a student in this program, I am focused on retinal development, but exposed to all kinds of questions, different approaches, and techniques in science. This gives me a well-rounded background and knowledge of what is relevant that I can apply to my work,” she explains.
Students in Hopkins’ biology Ph.D. program undergo four two-month rotations, and then choose what laboratory within those choices that they would like to specialize in for the remainder of their time at Hopkins.
Other rotations Eldred completed included studying differences between the left and right sides of the brain using zebrafish with Marnie Halpern, Ph.D.; in neurology working to understand how the pathways of hearing and vision are connected with Hey-Kyoung Lee, Ph.D.; and studying the microbiome and the different bacteria present in the vagina and how they contribute to women’s health with Richard Cone, Ph.D.
As an undergraduate biochemistry major at the University of Washington, Eldred worked in two separate labs: A neurology lab studying how specific brain neurons contributed to learning, and another lab that was part of the National Oceanic and Atmospheric Administration (NOAA) to study when toxic algae bloom and if we can predict it based on weather patterns.
She will be returning to the University of Washington this fall as a postdoc, working with Thomas Ray to pursue more retina-based questions. One of her projects will involve working to build a system within retinal organoids to see if what she’s done at Hopkins can be applied to fighting retinoblastoma.
A long-term goal of hers is to remain in academia; she enjoys both the teaching and research component. “I’m open to that changing, but that is currently the job I’ve seen that has the most things I’d like to do,” she says.