Sun. Feb 5th, 2023
The Nobel Prize goes to researchers who have figured out how our cells tell time

Today, the Nobel Prize Committee honored three American biologists for their role in unraveling one of biology’s earliest mysteries: how organisms tell time. Microbes, plants and animals all run on a 24-hour cycle, one flexible enough to gradually reset itself, though it can take a few days after a transcontinental journey. The biological systems responsible for maintaining this circadian clock require many proteins that undergo complex interactions, and the new laureates are being honored for their use of genetics to unravel 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 did not depend on daylight, but continued even if the plant was in non-stop darkness.

It would take nearly 250 years to move from this perception to a biological grasp of the system. The change, as so often, came about with the help of the fruit fly Drosophila. A genetic screen in the 1960s identified three different mutations that altered the circadian clock of flies: one that lengthened the 24-hour period, one that shortened it, and one that made it erratic. Mapping these revealed that they all affected the same gene. From there, however, the field had to wait 20 years before we developed the technology to clone the gene responsible for these changes, called period of time.

That is where the three new laureates come into play. Jeffrey Hall and Michael Robash, both of Brandeis University, and Mike Young of Rockefeller University succeeded period of time gene. In the beginning this helped very little. The protein that coded for it didn’t look much like anything we’d seen before, leaving us with little idea about its function.

But getting a sense of how it worked was possible. The messenger RNA produced by the gene, which is necessary for the period of time protein, was found to be in a 24-hour cycle, peaking in the early night. The protein itself showed a similar pattern, peaking at night. For much of the day, the protein resides in the body of the cell, but at night it makes its way to the nucleus, where it could participate in gene regulation.

Young’s lab thought so too period of time was not the only one to identify a gene called timeless that was also on a 24-hour cycle. Timeless mutations also interrupted an organism’s circadian rhythm. Crucially, Young’s lab showed that the protein made by timeless would interact with the period of time protein, making it more stable and allowing the complex to pass into the cell nucleus.

Find complexity

From here, the incremental nature of biology took over, as many different laboratories, using a variety of organisms, began to fill in the pieces, defining an incredibly complex clock system. Called a gene Clock found in mice. The protein made from it and its relative bicycle finally had the ability to bind to DNA, allowing it to regulate genes; the targets included the mouse versions of timeless and period of time. During the day, it activates these genes, leading to accumulation in the evening. Once the timeless and period of time proteins find their way to the nucleus, but they interact with the Clock proteins, which convert the complex into a repressor that turns off the genes.

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

The central cycle – from gene activators to repressors and back – is highly regulated. For example, there is a gene called double time that focuses on the period of time protein for destruction, causing levels to drop rapidly during the day and slowing down accumulation at night, sharpening the on/off difference. Some light-sensitive proteins called “cryptochromes” do similar things to timelessallowing the clock to reset itself to match the day/night cycle.

It is believed that the requirement for all these interactions to get the system working helps to keep it regular and protect it from minor changes.

The work has also revealed that virtually all animals share a similar system for controlling their internal clocks. But for complex animals, there is also a common coordinating clock (usually 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 tuned to local time.

While this system appears to have originated once in animal history, it is not the only clock on Earth. Plants seem to have developed their own system. Although it also shows a 24-hour oscillation of gene regulation, the proteins involved are different. A third system is also present in photosynthetic bacteria.

While this is quite clearly a win for the physiological side of “Physiology or Medicine,” the Nobel Foundation literature mentions that a number of human conditions involve dysfunction of our circadian rhythms. And when these go wrong, they alter many basic functions of the body, such as the regulation of metabolism, hormone levels and memory consolidation. Sleep problems are also typical features of depression and bipolar disorder. So while the three laureates probably weren’t thinking about medicine when they started screwing up fruit flies, their work may ultimately have some medical impact.

By akfire1

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