In a study published today in Nature, an international research team reveals how birds have solved a biological paradox. The researchers show that the inner parts of the bird retina operate under chronic oxygen deprivation, relying instead on anaerobic energy production.
At the same time, the study overturns a long-standing assumption about a mysterious structure in the eye that has puzzled scientists since the 17th century.
Most animals supply neural tissue with oxygen through dense networks of tiny blood vessels. This is considered essential, as neurons have an exceptionally high energy demand. The retina, a highly specialized extension of the brain, is no exception – and in fact consumes more energy than any other tissue in the body.
Birds, however, present a paradox. Their retinas are avascular, meaning they lack blood vessels within the retinal tissue itself. This feature is thought to improve visual acuity, since blood vessels scatter light in its path to the photoreceptor. But how the retina survives without a blood supply has remained unknown.
"Our starting point was simple," says biologist Christian Damsgaard, first author of the study and associate professor at Aarhus University in Denmark. "According to everything we know about physiology, this tissue should not be able to function."
While the starting point may have been simple, the journey to the end point was anything but simple. It has taken Damsgaard and a growing team of researchers, mostly from Aarhus University, 8 years to produce the results, that are now finally published.
No oxygen where it was assumed to be
For centuries, the prevailing explanation has been that a structure called the pecten oculi – a comb-like, highly vascularized organ protruding into the vitreous body of the bird eye – supplies oxygen to the retina. The structure has been known since the 1600s, but its precise function has remained speculative.
One reason, the researchers note, is that no one had directly measured oxygen levels in the bird retina under normal physiological conditions.
"Doing so is technically extremely challenging," says senior author Jens Randel Nyengaard, professor at Dept of Clinical Medicine, Aarhus University. "You need to keep the animal under stable, normal physiological conditions while performing very delicate measurements."
In 2020, the team was able to do exactly that, thanks to a collaboration with veterinary anaesthesia expert and assistant professor Catherine Williams, also from Aarhus University. The results were unexpected: the pecten does not deliver oxygen to the retina at all. Measurements showed that the inner layers of the retina exist in a state of permanent oxygen deprivation, with roughly half of the retinal tissue receiving no oxygen.
Each answer raised new questions
If the retina receives no oxygen, how does it produce enough energy to function?
To answer that question, the researchers embarked on a multi-year investigation combining physiology, molecular biology, imaging, and computational analysis. Progress was slow, in part due to the scale and complexity of the data – and in part due to the COVID-19 pandemic, which restricted laboratory access.
Using spatial transcriptomics, the team mapped the expression of thousands of genes across thin sections of the retina, allowing them to see where specific metabolic pathways were active within the tissue.
(Spatial transcriptomics is a technology that maps gene expression directly within intact tissues, revealing both what genes are active and where they are active).
"We were not looking at one or two genes, but at 5,000 to 10,000 genes at once, each mapped to a precise location," says Damsgaard. "That gave us a kind of molecular GPS."
The data revealed a striking pattern: genes involved in anaerobic glycolysis – the breakdown of sugar without oxygen – were highly active in the oxygen-deprived inner layers of the retina.
This finding, however, raised yet another problem. Anaerobic glycolysis produces roughly fifteen times less energy than oxygen-based metabolism per sugar molecule.
"This mismatch raised yet another question: How can one of the most energy-hungry tissues in the body survive on such an inefficient process?" Nyengaard says.
A new role for an old structure
The answer emerged through further imaging studies conducted in collaboration with metabolic imaging specialists. Using radiolabelled sugar and autoradiography, the researchers showed that the bird retina takes up glucose at much higher rates than the rest of the brain.
This led the team back to the pecten oculi.
By revisiting their spatial transcriptomics data, the researchers identified high expression of glucose and lactate transporters in the pecten. The structure, they found, serves as a metabolic gateway: delivering large amounts of sugar into the retina and removing lactate, a waste product of anaerobic metabolism, back into the bloodstream.
"The pecten is not an oxygen supplier. It is a transport system for fuel in and waste out," says Nyengaard.
The discovery fundamentally changes the understanding of a structure that has been misinterpreted for centuries.
"We are essentially collapsing one house of cards and replacing it with another. House of cards, because scientific findings are not set in stone. New results can add new knowledge. That is how science progresses," Nyengaard adds.
Evolutionary and medical perspectives
The researchers note that avoiding oxygen and blood vessels in the retina likely confers an optical advantage, improving visual sharpness. Evolutionary evidence suggests that this trait arose in the dinosaur lineage leading to modern birds.
While the study is purely fundamental research, the authors point out that the findings may have broader implications.
"In conditions like stroke, human tissues suffer because oxygen delivery is reduced and metabolic waste accumulates," says Nyengaard. "In the bird retina, we see a system that copes with oxygen deprivation in a completely different way."
"Nature has solved a physiological problem in birds that makes humans sick.We hope that understanding this evolutionary solution can inspire new ways of thinking about why tissues fail under oxygen deprivation in disease, and how such diseases can be treated" he adds.
