Today, the Nobel Prize committee has honored three US biologists for their role in unravelling one of biology's earliest mysteries: how organisms tell time. Microbes, plants, and animals all run on a 24-hour cycle, one that's flexible enough to gradually reset itself, although it can take a few days after transcontinental travel. The biological systems responsible for maintaining this circadian clock require a lot of proteins that undergo complex interactions, and the new laureates are being honored for their use of genetics to start unraveling this complexity.

A long-standing problem

The first description of an organism's internal clock dates all the way back to 1729, when a French astronomer (!?!?) decided to mess with a plant that opened and closed its leaves on a 24-hour cycle. He found that the cycle didn't depend on daylight but would continue even when the plant was kept in the dark nonstop.

It would take nearly 250 years to move from this observation to any sort of biological handle on the system. The change, as it has been so many times, was brought about using the fruit fly Drosophila. A genetic screen in the 1960s identified three different mutations that altered flies' circadian clock: one that lengthened its 24-hour period, one that shortened it, and one that left it erratic. Mapping these revealed that all of them affected the same gene. From there, however, the field had to wait 20 years for us to develop the technology to clone the gene responsible for these changes, named period.

That's where the three new Laureates come in. Jeffrey Hall and Michael Robash, both at Brandeis University, and Rockefeller University's Mike Young managed to clone the period gene. At first, this was very little help. The protein it encoded didn't look much like anything we'd seen before, giving us very little clue about its function.

But getting a sense of how it operated was possible. The messenger RNA produced by the gene, which is needed to make the period protein, turned out to be on a 24-hour cycle, peaking in the early night. The protein itself displayed a similar pattern, peaking at night. For much of the day, the protein is found in the body of the cell, but at night it makes its way into the nucleus, where it could participate in gene regulation.

Young's lab also found that period wasn't alone, identifying a gene called timeless that was also on a 24-hour cycle. Timeless mutations also interrupted an organism's circadian rhythm. Critically, Young's lab showed that the protein made by timeless would interact with the period protein, making it more stable and allowing the complex to transition into the cell's nucleus.

Finding complexity

From here, the incremental nature of biology took over, as lots of different labs, using a variety of organisms, began to fill in the pieces, defining an incredibly complex clock system. A gene called Clock was found in mice. The protein made from it and its relative cycle finally had the ability to bind to DNA, allowing it to regulate genes; its targets included the mouse versions of timeless and period. During the day, it activates these genes, leading to their accumulation in the evening. Once the timeless and period proteins make their way into the nucleus, however, they interact with the Clock proteins, converting the complex into a repressor that shuts the genes off.

This system also regulates a variety of other genes, allowing cells as a whole to respond to the time of day.

The cycle at the center of it—from gene activators to repressors and back—is highly regulated. For example, there's a gene called doubletime that targets the period protein for destruction, causing its levels to drop rapidly during the day and slowing down its accumulation at night, sharpening the on/off difference. Some light-sensitive proteins called "cryptochromes" do similar things to timeless, allowing the clock to reset itself to match the day/night cycle.

It's thought that the requirement for all these interactions to get the system to work helps keep the whole thing regular and buffers it against minor changes.

The work has also made it clear that pretty much all animals share a similar system for controlling their internal clocks. But for complex animals, there's also an overall coordinating clock (typically originating in the brain) that also influences the progression of individual cellular clocks. In humans, this master clock takes input from the retina to keep the body attuned to the local time.

While this system appears to have originated once in the history of animals, it's not the only clock on Earth. Plants appear to have evolved their own system. While it also shows a 24-hour oscillation of gene regulation, the proteins involved are distinct. A third system is also present in photosynthetic bacteria.

While this is pretty clearly a win for the physiology side of the "Physiology or Medicine," the Nobel Foundation's literature mentions that a number of human disorders involve dysfunction of our circadian rhythms. And when these go wrong, they alter many basic body functions, like regulation of metabolism, hormone levels, and memory consolidation. Sleep problems are also typical hallmarks of depression and bipolar disorders. So, while the three laureates probably weren't thinking medicine when they started messing up fruit flies, their work may ultimately have some medical impact.