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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?

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.

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.

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!

31 comments on “A Nobel for Circadian Rhythm”

  1. Luysii says:

    I can not think of a single physiological or biochemical human parameter that doesn’t show circadian variation. My freshman biology professor (Colin Pittendrigh) is up there smiling.

  2. Emjeff says:

    Well-deserved. This is a fascinating area of biology.

  3. luysii says:

    It is remarkable how fortunate I was 61 years ago as a freshman to have John Wheeler –https://en.wikipedia.org/wiki/John_Archibald_Wheeler — teach me physics, and Colin Pittendrigh — https://en.wikipedia.org/wiki/Colin_Pittendrigh — teach me biology. Dei sub nomine viget (translation: God went to Princeton)

    1. Peter S. Shenkin says:

      I thought it meant “God fidgeted in the classroom.”

      I did my doctoral work with Walter Kauzmann at Princeton. IIRC, there was also someone in the engineering school who had made a contribution to the study of circadian rhythms. Does that ring a bell to anyone?

      1. luysii says:

        Kauzmann’s book on Quantum Chemistry came out that year (1956), and he taught PChem to undergraduates, but there was no course in Quantum Chemistry offered to undergraduates.

  4. Wile E. Coyote, Genius says:

    Do permanent cave-dwelling organisms have circadian rhythms? Constant temperature and constant absence of light in those conditions.

    1. Peter Shenkin says:

      Good Q. Dunno. But surface-dwelling organisms, including humans, when placed into a cave for long periods of time, in isolation, and without time cues, do exhibit circadian rhythms. Individuals, left to their own devices, entrain to somewhat different schedules; some longer, some shorter than 24 hours, but usually off by a few hours at most. Still, it’s interesting that this occurs.

      I have the completely unsubstantiated idea that those with naturally long circadian periods are night owls who have trouble getting up in the morning and those with naturally short periods are the morning people. I can’t help thinking this and wonder if it’s true.

    2. Crocodile Chuck says:

      Yes, they do; & they ‘free run’ at a period of ~ 23 hours [reflecting the slowing of the Earth’s rotation over millennia]

    3. Anonymous says:

      I actually bumped into Rosbash at a seminar a few weeks ago and I asked him something similar. I was curious about organisms that might have evolved far, far away from direct solar cues, such as tube worms or other lower life forms in the ocean deeps. He wasn’t sure about tube worms. He did mention that blind cave fish and other “blind” species do have circadian rhythms. In the case of cave fish, he mentioned that although their rhythms are not directly linked to “light,” they are linked to daily fluctuations in the food supply (that could be responsive to solar) or other solar influenced cues. Based on all the current hubbub, it would seem that EVERY life form should display circadian rhythms but I’m still wondering about tube worms and other critters hovering about thermal vents. Can there be tiny fluctuations in that environment, maybe due to the earth’s rotation or tides, that can serve as an external clock?

      From another conversation with Rosbash many years ago (I forget what started it) he mentioned that while he was studying period (per) and timeless (tim) that he had two students, Per (from Norway) and Tim (from the US), that were studying per and tim. Sorry, it was much funnier in context.

      Jeff Hall is also an expert on the US Civil War and he taught a course in the history department (or whatever non-Bio dept it would be).

    4. Karl Dall says:

      reindeer = no proper input from the sun, so they lost circadian rhythm

  5. Anon says:

    I remember the first time I completely screwed up my circadian rhythm – when I wrote my entire PhD thesis in just 5 days, from Monday morning to Friday night without sleep, and only a quick shower as my only break. And of course on Friday night I had to go out and get pissed. I didn’t wake up until Sunday evening, and then couldn’t go back to sleep. Aarrgghh!

  6. mallam says:

    Certainly well deserved. What area will the Chemistry award honor this year? Personally, I’d like to see Caruthers for DNA synthesis.

  7. Daniel Barkalow says:

    When they called Rosbash to tell him he’d won the Nobel prize at 5 am his time, he reacted with disbelief. However, when he was told at other times of the day, he exhibited different behavior…

    1. Insilicoconsulting says:

      Priceless! hahaha

    2. J Severs says:

      Well done 🙂

  8. Bla says:

    I hope to god CRISPR gets the chem Nobel at some points, just to hear the howls of “That’s not chemistry!” again.

    1. Pennpenn says:

      Eh, everythings chemistry when you boil it down enough- literally and figuratively.

  9. a says:

    I’m not worried about crispr getting the Nobel yet – still plenty of time to see if that will hold up, or if the off target effects will doom it to being just a research tool. And Doudna and Zhang are doing great

    I am getting impatient for Jim Allison to win it, though. IO is the biggest thing in medicine in the past 30 years, and he is aging really fast (evidently partly due to his own cancer).

    1. Given how many “only a research tool” have won Nobels by having impacts not nearly as huge as CRISPR/Cas9 on research, that’s hardly an excuse to discount it.

      Therapeutic application via gene therapy gets the headlines — particularly with the patent battle — but the myriad applications of rapidly re-programmable DNA cleavases, nickases and binding proteins are much greater.

  10. Barry says:

    The PER clock seems a perfectly satisfactory explanation for an endotherm, or for a fruit-fly in a lab at constant temperature. But it escapes me how that can work for an ectotherm outside such a controlled environment. The rxn rates are going to change with temperature, and the cycles won’t be even approximately circadian.
    What am I missing here?

    1. Anonymous says:

      “What am I missing here?”

      That the biology of life is far more complicated than reductionist models that explain a lot, but not all, of How Things Work.

    2. Chris Phoenix says:

      When it comes to complicated molecular machines, it’s not obvious to me that reaction rates have to change with temperature (over a limited range that the organism has evolved to be functional in).

      Proteins are full of entropic springs (yes, it’s a thing, e.g. in latex rubber), which do indeed change their “spring constant” with temperature. An enzyme which cycled much slower than thermal noise could be tuned to do almost anything – for example, a spring somewhere in the enzyme’s backbone could deform it at higher temperature, slowing its reaction rate.

      It wouldn’t surprise me if, somewhere in the chain of events that implement the circadian rhythm in ectotherms, there’s a reaction which does not follow Arrhenius, in a way that compensates for temperature effects elsewhere in the chain. (Note that enzymes do not always increase their activity in proportion to temperature: http://academic.brooklyn.cuny.edu/biology/bio4fv/page/enz_act.htm )

      Some old (and somewhat amateurish) but still interesting writing of mine on entropic springs: http://www.crnano.org/essays05.htm#4

      (It also wouldn’t surprise me if one reason endotherms are successful is that their protein machines don’t have to be as finely tuned over as wide a range of conditions.)

    3. Anon says:

      Barry, that’s a great question. The circadian clocks are temperature compensated so that the period is relatively stable across a range of temperatures. Some of the mutations that cause changes in period length also impact temperature compensation.

      1. Barry says:

        Apparently temperature-compensation for the PER-TIM clock is subtler than was once thought

        Retraction: PER-TIM Interactions with the Photoreceptor Cryptochrome Mediate Circadian Temperature Responses in Drosophila
        Rachna Kaushik, Pipat Nawathean, Ania Busza, Alejandro Murad, Patrick Emery, and Michael Rosbash

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767707/

  11. gippgig says:

    I wonder if PER & TIM are resistant to translation inhibition by the unfolded protein response.

  12. Vinod Jairaj says:

    This is very interesting! Congratulations to the winners!!

  13. artkqtarks says:

    I always thought that the discovery of the mutants by Konopka and Benzer was the big breakthrough.

    Hall, Rosbash, and Young made great discoveries and we now have a good understanding of circadian rhythm because of them. But they were trying to win a race with a clear goal. They must have worked very hard to win, but they knew there was a goal because of the surprising discovery by Konopka and Benzer.

    I think Benzer deserved a Nobel Prize. He could have shared the Nobel Prize with Kandel because Benzer’s work also touched on learning and memory. Maybe Benzer’s discoveries were not decisive enough to persuade the committee. Maybe he didn’t lobby to win the prize. But he certainly had a huge impact.

    1. GCC says:

      For anybody interested in this early work, I would definitely recommend Jonathan Weiner’s book about Seymour Benzer called Time, Love, Memory. It’s one of my favourite scientific biographies.

  14. a says:

    It is about time.

  15. Chemcat says:

    Until I started working part-time on the night shift in addition to my regular nine-to-five, I admit I did not give the complexity of the circadian rhythm its due consideration. Speaking anecdotally, I feel rather cold when I work a night shift on little sleep, and when I end the shift, my eyes just… hurt. I seem to do well transitioning from the night shift to the day if I stay in areas using artificial lighting, but I feel drained of energy when I step into bright, natural daylight. I was interested to learn here about the genetic ebb and flow behind the circadian rhythm, and that daylight exposure does not play the role in sleep-wake patterns that I thought it did.

    A quick literature search of “immunology circadian rhythm” will make for fun lunch break reading for me….

    Congratulations to Rosbash, Hall, and Young on their well-deserved recognition.

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