Rhythm and blues – and jet lag, too

Provencio.
Photo by Jack Mellott.

Frequent fliers would love to get their hands on a pill that relieves jet lag -- the fatigue and mental fuzziness that can occur after rapidly traveling across multiple time zones. Although such a quick fix might sound too good to be true, it’s not unthinkable, thanks to research into light-controlled physiology led by biology professor Ignacio Provencio.

Provencio explains that a great deal of human physiology is controlled by light -- vision, for one. But light also controls processes that are completely independent of image formation, such as resetting the body’s circadian rhythms -- metabolic and behavioral patterns that repeat in roughly 24-hour cycles. Because jet lag is thought to result from a disruption of circadian rhythms, understanding the mechanisms underlying these rhythms holds the potential for developing ways of, for example, artificially resetting the body’s internal clock when one lives in D.C. and travels to L.A.
 
“Circadian rhythms persist for a period close to 24 hours, but they are not exact. It’s like having a watch that goes a little too fast or a little too slow. It has to be reset on a fairly regular basis to be effective,” says Provencio. “For a long time, a big question in the field was ‘What are the cells within the eye that are detecting light and resetting the clock?’”

Until very recently, rod and cone cells, which are located in the retina, were the only known photoreceptors. In the mid-90s, when he was a doctoral student at U.Va., Provencio and his colleagues demonstrated that animals missing rod and cone cells (and consequently blind) have no disturbance to their circadian rhythms or other light-controlled physiological responses. This prompted them to hypothesize that another photoreceptor in the eye must be responsible for detecting changes in ambient light and resetting the clock.

“This generated quite a stir, because people have studied the eye in incredible detail for over 150 years; it’s one of the most studied organs in the human body. So for us to postulate that another photoreceptor in the eye had been overlooked was a bit heretical,” Provencio says.

In 1998, while he was doing postdoc work at the Uniformed Services University, Provencio and his colleagues identified a novel light-sensitive protein, which they named melanopsin, in the skin cells of the African clawed frog. They also found melanopsin in the frog’s retina, but not in the rod and cone cells. “We thought ‘Aha!’ If we can find a mouse or human version of this protein, it also might be in a non-rod, non-cone cell and be a candidate photoreceptor that regulates circadian rhythm.

“Sure enough, we found a mammalian version of melanopsin, and it was only made in one place -- the retina. But not in rods and cones,” says Provencio. Melanopsin subsequently was found in some retinal ganglion cells, a mass of neuron cell bodies that transmit visual image information to the brain. “These cells are essential to conscious vision, but apparently also play a role in subconscious physiological responses to light,” says Provencio.

Roughly 1.2 million ganglion cells exist in the human retina. Of these, only about 2,000 contain melanopsin and are anatomically inconspicuous as photoreceptors, unlike the 110 to 125 million rod and 6.4 million cone cells, whose shapes are distinctive. Yet when Provencio used a reagent to view the melanopsin-containing cells, he found that collectively they create a “net” that captures the light used for non-image-forming processing.

Once the photoreceptors were identified, Provencio and his colleagues teamed up with the Scripps Research Institute to demonstrate how the newly discovered sensory system regulates circadian rhythms. Provencio compared mice with melanopsin to “knock-out” mice, which were genetically altered to have no melanopsin. “The knock-out mice had big problems resetting their clocks,” says Provencio. Furthermore, they found that mice lacking melanopsin as well as their rods and cones were “completely insensitive to light by every measure,” he adds. The finding was so big, it was heralded a “top 10 breakthrough of 2002” by Science magazine.

Since this landmark discovery, Provencio has set out to “figure out the details” of this new photoreception system. He returned to U.Va. in December 2004 as an associate professor, and his research team is currently looking at polymorphisms of melanopsin to see how genetic variations may or may not affect cell function.

Provencio illustrates the implications of this research: “The gold standard treatment for people with seasonal affective disorder is light therapy, which suggests that some photoreceptors, possibly melanopsin cells, are not working to full capacity. Could this insensitivity to light be the result of a mutation in melanopsin?” he asks.
 
Furthermore, Provencio questions, “Do some people have better melanopsin systems than others?” which would explain why some people have less difficulty adjusting to changes in time zone. “We know that light affects melanopsin, and melanopsin initiates a chemical cascade inside cells. So, for people more affected by jet lag or for those who are relatively insensitive to light and perhaps likely to develop seasonal affective order, in theory, we can create a pill that initiates the chemical cascade directly, bypassing light altogether,” he says.