What Lies Behind Your Eye Color

The Kynurenine pathway’s role in determining an individual’s retinal health is becoming clearer, and it goes to show that someone’s ocular color pigment plays a bigger role than just assumed personal characteristics.

by Andrew Sweeney

Did you know that according to the ancient Greeks, blue eyes were seen as a sign of cowardly, barbaric nature, as opposed to the more common light brown of old Athens and Sparta? Of course, we’re also familiar with a different interpretation of the significance of this shade of color as propagated by a certain 20thcentury Austrian political activist… Thankfully, such nonsense doesn’t have much currency in the modern day.

Throughout human history, cultures have ascribed values, characteristics, and important associations with eye color for various pseudo-scientific reasons. Could the same issue have real ramifications for our ocular health, too?

According to a group of researchers based at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, the color of one’s eye could well have a considerable impact on retinal health.

Their recently published research paper, Modulating the Kynurenine Pathway or Sequestering Toxic 3-hydroxykynurenine Protects the Retina From Light-Induced Damage in Drosophila,* examines the Kynurenine pathway’s (KP) role as an evolutionary conserved metabolic pathway that regulates a variety of biological processes. Comprised of a number of chemical elements within cells, the pathway has a considerable influence on much of the body’s key functions.

According to the researchers, as it turns out… humans and flies have a lot in common.

The research examines retinal homeostasis in the context of light stress in Drosophila melanogaster cinnabar, cardinal, and scarlet, which are fly genes that encode different steps in the KP.

Yes, you read that right, fly genes! As it turns out, the KP is preserved in flies as much as it is in humans, allowing scientists to extrapolate their research results and postulate a similar conclusion for humans. Furthermore, in both flies and humans, the severity of a mutant phenotype/symptoms in individuals carrying the same mutation can be highly variable, ranging from complete neuronal degeneration to weaker manifestations of a given disease phenotype.*

The researchers from Dresden proposed that given that the KP not only participates in brown pigment formation but is also part of metabolic processes in cells, the role of Drosophila w (found in the fruit fly and was the first sex-linked mutation discovered) in predisposing eyes to degeneration is linked to an imbalance in some KP metabolites, rather than to its role in pigment biosynthesis — and hence shielding the eye from excess light.

They pointed to the fact that mutations in Drosophila w, which lack all pigments and make the eyes white in color, modulate retinal degeneration in flies expressing the human Tau protein to back up their proposal. To investigate further, they examined genetic interactions, biochemical analysis of metabolites, and dietary intervention.

By devising a technique for analyzing the biochemical makeup of Kynurenine pathway metabolites, the researchers were able to correlate varying metabolite levels with the overall health status of the retina — and it should be noted that this represented a novel technique. They subsequently discovered that a specific metabolite, 3-hydroxykynurenine (3OH-K), has a detrimental effect on the retina.

Furthermore, they were able to demonstrate that the extent of degeneration is impacted by the equilibrium between harmful 3OH-K and beneficial metabolites, such as Kynurenic acid (KYNA).

The researchers also administered two of these metabolites to normal (non-mutant) flies and observed that 3OH-K amplified stress-induced damage to the retina, whereas KYNA prevented stress-related damage to the retina. This finding implies that the ratio of Kynurenine pathway metabolites can be modified to enhance retinal health in specific circumstances. The researchers also found that targeting these four genes, which represent four distinct stages within the pathway, affects not only the concentration of 3OH-K itself, but also its location in the cell and its accessibility in subsequent reactions, highlighting its significance for retinal health.

In their concluding remarks, the researchers stated that their study demonstrated the significance of the KP not just for pigment production, but also for maintaining healthy retinas via the roles of specific metabolites. They added that in the future, therapeutic approaches targeting the KP should consider the ratio of different metabolites and their respective locations and functions in order to address disorders associated with impaired KP activity, as seen in a range of neurodegenerative conditions.

Finally, the German scientists shared that the increase of free 3OH-K is clearly detrimental to retinal health, and that they had unraveled the importance of compartmentalization of the KP metabolites as a protective mechanism.

Therefore, we can say that the pigmentation that determines your eye color plays a role in the health of your retina. This is a fascinating area of study, and we look forward to hearing more about it in the future. Who knows, maybe there was an ancient Greek philosopher who postulated that eye pigment has more to do with retinal health and less to do with baby blues making you more likely to run from a fight.

We thank the German researchers and their humble fly volunteers for their contribution to medical science and retinal health.

* Hebbar S, Traikov S, Hälsig C, Knust E. Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila. PLoS Genet. 2023;19(3):e1010644.