A Nobel For Circadian Rhythm

How many people had their bets down on circadian rhythm for the Medicine/Physiology Nobel this year? Not many, I’d think, and that includes one of the actual laureates. The three winners are Michael Rosbash and Jeffrey Hall of Brandeis (a university that I can literally see outside the window of my train as I write this post!) and Michael Young of Rockefeller. When the committee called Rosbash, according to Stat, he responded with “You are kidding me.”

That’s not because it isn’t a great discovery, but it’s just one of the many “Nobel-able” ones out there that doesn’t have as high a profile as (say) CRISPR gene editing, which is where a number of observers expected an award. (There’s always time for them to give that one as the Chemistry prize on Wednesday, or of course to do no such thing and just sit on it for a few years in the way that Nobel committees do – we’ll see!).

Circadian rhythm, the “internal clock” of humans and other organisms, is one of those topics that seems obvious for a few seconds, and then starts to get complicated. It’s clear that we humans have a day/night wake/sleep cycle, but how does that work? You’d think, well, sure, it’s the amount of daylight that we’re responding to, but we still have similar behavior under artificial lighting, and dark, cloudy days don’t seem to reset us, either. Experiments with both animals and human volunteers completely sealed off from daylight and able to set their own activities show that they also have sleep/wake cycles very close to 24 hours. Well, sure, then, you think, it’s physical activity. But doing a hard day’s work as opposed to lounging around doesn’t seem to affect things as much as that guess would require. All right then, it’s just duration: you can only be awake so long before going back to sleep, and you can only be asleep so long before waking up. But that just raises the basic question again: how does your body know how long it’s been awake? Or asleep?

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Hall, Rosbash, and Young worked out different parts of that puzzle. As usual, it’s rather hard to do that in humans, for a lot of excellent reasons, so a lot of the key discoveries were made in Drosophila (fruit flies). That illustrates another thing about “chronobiology” – evolutionarily, it goes way back. Organisms have been responding to the day/night cycle for an awfully long time, and the mechanisms behind it definitely show that ancient lineage. The first “clock mutants” in fruit flies were noted in the 1970s by Ron Konopka and Seymour Benzer, both deceased and thus Nobel-ineligible. By deliberate exposure of flies to mutagens, they isolated some strains with lengthened schedules, some with shortened ones, and some where the rhythm had been disrupted completely. All of these mapped to the same gene, which was named period.

That actually was a huge deal, because there had been (and to some extent still is) a fierce debate about the effect of genes, especially single genes, on an organism’s behavior. period was (as far as I can tell) the first single gene that absolutely affected something that was clearly classes as “behavior” (wake/sleep cycling), and showed that under the right circumstances it really could come down to that level. Interestingly, the protein that period codes for (PER) turns out to be mostly located in the nucleus. Hall, Rosbash, and Paul Hardin closely tracked the amounts of the protein and its associated mRNA, and found that each of these cycled very regularly, with about a six-hour delay between peak mRNA levels and peak Per levels. Another mutated fruit fly gene that affected their cycles, clock, turned out to be involved in transcriptional control in this system via its protein CLK, as did timeless, a gene that codes for the TIM protein in the work from Young’s lab (with Jeff Price). There’s another gene in the mix called cycle as well, encoding the protein CYC.

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To just jump into the whole machine at one point, PER and TIM proteins build up in the cytoplasm as they’re synthesized. As their concentration increases, they get taken into the nucleus. CLK and CYC are in there already, attached to particular stretches of DNA and activating them for transcription. PER associates with them, and the new complex falls off DNA, thus shutting off transcription of the genes downstream of them: those genes include period and timeless themselves. So, via the CYC/CLK proteins, PER and TIM shut down the production of more PER and TIM, and their concentrations head back down. That’s the feedback loop, and the rest of it is set up by degradation and resynthesis of the various proteins themselves. All proteins in a cell have a finite lifetime, and as PER and TIM get cleared out, CYC and CLK can come back and set off their synthesis once more, whereupon PER and TIM proteins build up in the cytoplasm, and here we go again. There are all sorts of subtle additions to this process – for example, it turns out that in fruit flies, the light-responsive cryptochrome pigment can bind to TIM and mark it for faster degradation (that’s how light cues can reset, to some extent, fruit fly rhythms). Here’s a video from HHMI that goes through the whole process.

Mammalian protein rhythms work somewhat differently, although very much along similar feedback principles and generally involving the human homologs of the fruit fly genes. So that’s where the clock is – in the rates of protein synthesis, transport, binding, and degradation. The various protein and mRNA levels go up and down like the elements of a watch mechanism, day in and day out throughout an organism’s entire life. The number of genes and proteins affected by this clock is huge – in humans, it’s well established that blood pressure, gut activity, heart rate, metabolic rate, hormone levels and many others are tied to this system, via the operation of the protein clock in the different tissues involved. Anyone who’s had a night-shift job or experienced a bad case of jet lag can appreciate the number of key physiological processes tied to circadian rhythm, going all the way up to higher cognitive functions. These connections are still an extremely active area of research, with implications for public health, drug research, and modern industrial society in general.

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So even those who didn’t have circadian clocks on their Nobel list should have no problem with the prize being awarded. The only problem is that this is one of those fields – and there are many – where there are more names than Nobel slots, even with the passing of Konopka and Benzer. Congratulations to all involved!

Disclosure: None.