Apple snail eye regeneration offers new insights into human sight restoration

The eye of the apple snail is unusually similar to a human eye-but, unlike human eyes, it can regrow itself if injured or even amputated. New research from the Stowers Institute for Medical Research has established the apple snail as a novel research organism to study eye regeneration, with the potential to better understand and find treatments for eye conditions in humans like macular degeneration.

The study, from the lab of Stowers President and Chief Scientific Officer Alejandro Sánchez Alvarado, Ph.D., published in Nature Communications on [date], describes a new system to study sensory organ regeneration in the apple snail, Pomacea canaliciulata. Led by former Postdoctoral Research Associate Alice Accorsi, Ph.D., now an Assistant Professor at the University of California, Davis, the research team discovered that the apple snail has complex camera-type eyes like humans and also developed tools to alter its genome, resulting in snails with stable gene variations that can help researchers better understand the process of regeneration.

"Our eyes are extremely important for perceiving our environment, yet when damaged are unable to recover," said Accorsi.

Essentially we had no way to identify solutions for treating conditions like retinal degeneration or physical injury to the eye. But nature has answers for us. We now have a tractable system for investigating which genes are responsible for camera-type eye regeneration."

Alejandro Sánchez Alvarado, Ph.D., Stowers President and Chief Scientific Officer 

The process of apple snail eye regeneration from amputation to full restoration occurs in four stages over 28 days: wound healing, formation of a special cell mass, emergence of a lens and retina, and the maturation of all eye components. Because vertebrates including humans can only perform the first stage, wound healing, the researchers are looking at where regeneration and development diverge and are trying to identify what switch snails use to reactivate new eye development.

Apple snails have eyes that are anatomically similar to vertebrate eyes, including those in humans, with a lens, cornea, and retina. The researchers identified that a gene called pax6-known to play a crucial role in vertebrate and fruit fly eye development-is also present in apple snails. 

"A key gene governing eye development in vertebrates is pax6, and we showed for the first time that apple snails not only have pax6 but also that this gene is critical for their eyes to develop," said Accorsi.

In the lab, the team optimized the gene-editing technique CRISPR-Cas9 for apple snails that allowed them to disrupt pax6 gene function. The new line of snails was healthy yet noticeably missing their eyes.

"There were two big moments where I felt this was something that could be important for the entire scientific community," said Accorsi. "The first was discovering that the snail eye was just like a human eye. The second was observing these tiny embryos without eyes after disrupting pax6, and realizing we can use snails as a system for understanding gene function." 

"To have a research system that regenerates eyes, combined with the ability to do genetics in that system is among the first efforts in the history of science to gain a mechanistic understanding of the processes that underpin the restoration of a sensory organ as complex as the eye-from injury all the way to its regeneration," said Sánchez Alvarado.

Angus Davison, Ph.D., a professor at the University of Nottingham commented on the potential of the study. "Previously, progress in understanding mollusks and their genomes has been limited because there is no widely used genetically tractable species," he said. "This work showcases the potential of apple snails as a novel system to uncover the genetic mechanisms behind mollusk development."

For each stage of eye regeneration, the team collected and analyzed gene activity. This information about the timing of gene expression can be used to narrow down which genes are likely most promising for eye regeneration. 

"We now have a list of candidate genes," said Accorsi. "Going forward, we plan to disrupt these genes to test if they are required for regeneration and development of the eye."

"With a little bit of effort, a little bit of ingenuity, and a great deal of persistence, biology that seemed inaccessible is no longer a pipe dream," said Sánchez Alvarado. "Our work with the apple snails is proof positive-it really is possible to bring something that was far beyond what we thought we could do into the realm of real possibility to advance biological knowledge."

"It was a big risk," said Sánchez Alvarado. "But it worked."