Shaping the Eye for Perfect Vision

As the eye grows during childhood, it must grow in a way that preserves sharp, focused vision. If the eye becomes too elongated for its optical power, it can’t focus on distant objects (aka nearsightedness or myopia); if it grows too little, the eye can’t focus on nearby objects (aka farsightedness or hyperopia).

But the mechanisms that control eye growth have been surprisingly difficult to identify.

Ophthalmic researchers at Columbia University Irving Medical Center have now discovered that there are two sets of signaling pathways in the retina that control eye growth during childhood to ensure that vision remains sharp.

Based on their findings, the researchers are now looking for drugs to prevent nearsightedness and have identified more than 100 compounds with potential.

Why do we need to prevent myopia? What’s wrong with glasses?

“Nearsightedness, unlike farsightedness, raises the risk of developing serious eye problems later in life,” says the study’s lead author Andrei V. Tkatchenko, PhD, an associate professor of ophthalmic sciences at Columbia University Vagelos College of Physicians and Surgeons.

Though nearsightedness can be corrected with glasses, contact lenses, or refractive surgery (which alters the shape of the cornea), none of these solutions prevents excessive elongation of the eyeball. And it’s the excessive elongation of the myopic eye that raises the risk of developing serious eye conditions, such as retinal tears, cataracts, and macular degeneration. The risk increases with the degree of nearsightedness.

Nearsightedness is becoming more common, putting more people at risk of vision loss due to these serious complications. In the past 40 years, the number of nearsighted adults has increased from 25 percent to approximately 45 percent in the United States and has reached 80 percent in parts of Asia. By 2050, up to half the world’s population is predicted to be myopic.

Efforts to develop treatments to prevent or reduce nearsightedness have been limited by a lack of understanding of the mechanisms that control eye growth and optical development during childhood.

Most young children are born slightly farsighted. And then…

In most children, the eye grows so that images become focused precisely on the retina. As growth continues, the size of the eye may become too short or too long, which places the image either behind or in front of the retina.

Until early adulthood, the eye can compensate for these focusing errors by either increasing or decreasing its growth rate respectively. This process is thought to be controlled by the retina, although the exact mechanisms have been a matter of debate.

“Environmental factors, such as sustained ‘nearwork’—looking for hours at a computer screen or reading—are thought to place images slightly behind the retina and play an important role in the development of common nearsightedness,” Tkatchenko says.

“These factors seem to be driving the increases in myopia prevalence we see in many places around the world. They work by interacting with hundreds of genes and complex genetic networks that control the growth of the eye during childhood and account for most of the variance in refraction.”

What’s new

The researchers found that two distinct sets of pathways control eye growth in response to optical defocus; one set responds when the image is placed behind the retina, the other when the image is placed in front of the retina.

In the study, the researchers fitted lab animals with contact lenses that focused the image either behind the retina (farsighted defocus) or in front of the retina (nearsighted defocus). After 10 days or five weeks, the animals’ retinae were examined for changes in gene expression. The researchers found that the activity of hundreds of genes changed in the experimental animals compared to controls, with little overlap between the two sets of genes underlying response to different focusing errors.

From these changes in gene activity, the researchers were able to describe two distinct signaling systems in the retina, one that stimulates eye growth in response to farsighted defocus and another that suppresses eye growth in response to nearsighted defocus. The balance between these systems is thought to regulate growth of the eye during childhood.

“The prevailing wisdom held that the retina responds to the farsighted and nearsighted focusing errors by changing expression of the same genes but in opposite directions,” Tkatchenko says.

“Our study shows that the retina distinguishes between farsighted and nearsighted focusing errors by activating two largely different signaling systems.”

What’s Next

The Columbia researchers are currently searching for drug compounds that can modulate the two signaling systems that control eye growth in response to focusing errors. More than 100 compounds have been identified thus far, several of which are being tested in animal models of nearsightedness.

Caveats

Considering that only two time points were tested, the researchers suspect that refractive eye development may be regulated by additional genes and pathways, which could be identified with additional experiments.

More Details

The study, “Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth,” was published Oct. 9 in PLOS Biology.

Andrei V. Tkatchenko, PhD, is associate professor of ophthalmic sciences (in ophthalmology and pathology & cell biology) at Columbia University Vagelos College of Physicians and Surgeons.

Other authors: Tatiana V. Tkatchenko (Columbia University Vagelos College of Physicians and Surgeons); David Troilo and Alexandra Benavente-Perez (SUNY College of Optometry, New York, NY).

The work was supported by the National Institutes of Health (grants R01EY023839, R01EY011228, P30EY019007) and Research to Prevent Blindness.

A provisional patent application related to the findings has been submitted by Columbia University.