Cell Shorts | Building a better model of blindness and eye disease

Researchers at the University of Washington are working on growing human retinal tissue in the lab to better understand macular degeneration, glaucoma and other vision disorders

March 3, 2021

A retinal organoid grown in the lab from human stem cells grows early photoreceptors (magenta), the light-sensing cells of the retina, after about two months. University of Washington researchers are using cells gene-edited at the Allen Institute (green) to help develop these mini-retinas. Image courtesy of Akshayalakshmi Sridhar/University of Washington.

Imagine looking at the face of a family member and seeing only a dark blur. Or trying to read this article but when you look head-on at a word, the lines of individual letters shift out of focus.

These are the symptoms of macular degeneration, one of the most common forms of age-related vision loss. In its most severe forms, a person can lose almost all of their central vision, retaining only peripheral vision. Macular degeneration is a slow break-down of the macula, a small but important feature of the eye that gives humans our keen eyesight.

We are among the few animals that have a macula, making human vision — and human eye diseases — difficult to study in the lab. The macula is nestled in the center of the back of your eyeball, a small region of the retina, the part of the eye that detects light and lets us see the world around us. The macula holds a high concentration of cones, the specialized eye neurons that respond to light and initiate the signals of light and dark that ultimately pass to the brain via other retinal cells and the optic nerve.

University of Washington researchers Akshayalakshmi Sridhar, Ph.D. and Tom Reh, Ph.D., who is also an Allen Distinguished Investigator, want to better understand the human retina and the diseases that afflict it, including macular degeneration and glaucoma, a disease that causes damage to the optic nerve and is also linked to aging.

It's a tough problem to tackle, given that rodents don’t have a macula, and neither do the majority of the other commonly studied laboratory animals. The few non-human animals that have keen vision close to ours — some monkeys, eagles, a few types of lizards — aren’t possible to study in the lab the way Reh and Sridhar want to.

The UW scientists’ ultimate goal is to run large numbers of experiments that would allow them to pinpoint causes, or even potential treatments, of different kinds of human vision loss or blindness.

Lab-grown retinas

Enter organoids, miniature versions of organs grown in the lab from human stem cells. In the last decade, organoid research has grown in popularity as researchers figured out how to spur ever more types of tissue growth from the same starter cell population. Generally derived from an adult donor’s skin cells, naïve adult stem cells have the potential to develop into many other types of cells — or even multiple different kinds of cells that come from the same developmental source, in the case of organoids.

Sridhar is making retinal organoids grown from Allen Institute cell lines (green) fused with real human retinas (blue cells without any green) in the hopes of understanding how to make more lifelike retinal organoids. Image courtesy of Akshayalakshmi Sridhar and Alexandra Haugan/University of Washington

Although no organoid is a perfect copy of the real version, many of the tiny tissue blobs develop different layers of cell types and even different structures, making them a more lifelike substitute for modeling actual human organs than studying single cells growing in a petri dish. Sridhar and Reh wondered if retinal organoids could be used to study human-specific eye diseases like macular degeneration or glaucoma. The retinal organoids they and other scientists were able to grow in the lab, however, were missing certain key features.

As the little tissue blobs developed, their outer layers looked good — like real human eyes, they developed photoreceptor cells that specialized into rods and cones. But what should have been orderly layers of different specialized cells under the photoreceptors were a bit of a mess in the organoids, the scientists found. They were missing certain specialized groups of cells known to be important in eye diseases like macular degeneration and glaucoma.

Recently, Sridhar, Reh and their colleagues published a study outlining exactly where retinal organoids mirror and differ from their real-life counterparts, developing human retinas. They wondered if the problems could arise from the artificial conditions organoids are grown in, but when they kept real retinas alive and growing in the same lab conditions, their inner layers and structures looked just fine.

“So it’s not just the lab conditions, there’s something more that’s contributing,” Sridhar said. “That’s what we’re trying to figure out now.”

Fusion experiments

She suspects it might have something to do with certain support cells that are present in developing human eyes but missing in organoids. To figure out how to grow better retinal organoids, Sridhar is creating tiny fusions in the lab that blend retinal organoids and real human retinas. If the organoids are missing a key cell type or molecule, could the human tissue supply that support? She and her colleagues want to use these fusions to pin down the missing factor, and then figure out a way to engineer it into organoids, since studying the human tissue itself at large scale also isn’t feasible.

Sridhar needed a way to distinguish the different kinds of cells in her fusion experiments, real human retinal cells vs. organoid cells. That’s where cells from the Allen Cell Collection, the Allen Institute’s collection of gene-edited stem cell lines, came in. The cell lines are engineered to produce fluorescent tags on different internal cell structures. In her case, Sridhar needed a label that was bright and consistent — she needed a label to distinguish organoid cells from non-organoid cells, which are not labeled. The team used a cell line engineered to light up the borders of the nucleus, the large center structure of the cell that houses its chromosomes, which fit the bill of letting them sort out which cells came from real retinas and which from the organoids.

The fusion experiments are just getting off the ground. The researchers are in the early days of testing their theories on what might make a better retinal organoid. They’ve also made some observations that they didn’t expect — for example, the human tissue and organoid tissue stay in discrete compartments, rather than blending. It’s too soon to say whether the human tissue will give the organoids enough of a boost to fix their inner layers entirely, but their preliminary results are looking promising, the researchers reported.

Reh’s plans for discovery once they have a better retinal organoid in plan are ambitious. They want to use the tiny pseudo-retinas to better understand many human eye diseases, and to understand how age wreaks havoc on our vision. These two large goals are closely linked — many eye diseases, glaucoma and macular degeneration included, are linked to age. The neurons in the retina seem to degenerate over time, but it’s still not clear what causes that degeneration or why some elderly people suffer vision loss and some don’t. Eventually, they could also grow retinal organoids from patients’ own stem cells, to study genetic forms of vision loss and blindness.

To really understand age-related vision loss, the scientists want to speed up aging in the organoids, since the tiny retinas age at the same rate we do — and nobody wants to wait 80 years for the results of an experiment. Reh is collaborating with UCLA aging researcher Steve Horvath, Ph.D., who is also an Allen Distinguished Investigator, on some ideas that could accelerate retinal organoid aging.

“If we had a better retinal organoid system, you could run mini-trials in a petri dish. And then you could potentially get approval for later-stage clinical trials in humans much faster, and ultimately get treatments to all patients faster,” Reh said. “That would be my dream. I don’t know if we’re going to get there any time soon, but I do think we’re now seeing the beginning of using stem cell-derived organoids for disease modeling and drug discovery.” — written by Rachel Tompa, Ph.D.

Rachel Tompa is Senior Writer at the Allen Institute. She covers news from all scientific divisions at the Institute. 

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