Inner Clocks and Jetlagged Hamsters

I just got off a 20hr flight that I didn’t actually want to be on and my trip still seems far from over. I’ve been on the road for over 30hrs by this point and have officially had enough. Unfortunately there’s still a plane and a bus to catch after this. Over the past hours, I’ve had more than enough time to contemplate jetlag and sleep deprivation. Seeing as it’s about to take a massive toll on my brain and body, I might as well be scientifically prepared for what’s about to hit me. So I went on a hunt to find out the story behind the discovery of our internal clock and I found a story, which gave me a good insight into clever experimental planning. That´s something we can all learn from, no matter if scientist or not. So, how did scientists discover what made a jetlagged hamster tick out of time?

It all started out with luck. Serendipity plays a bigger part in scientific discovery than most scientists and their meticulous planning might lead you to assume. But time and time again, it has given us beautiful insights into the workings of nature. Just think of the man who was working with his bacteria, sneezed on his experiments, and discovered the first antibiotic, penicillin! Alexander Fleming got lucky. So did the man who discovered the cells responsible for our inner clock, the circadian rhythm.

Michael Menaker had been ordering golden hamsters for his students’ chronobiology experiments from the same commercial company for years. In his lab rotation, students each cared for their own hamster, and studied their activity patterns. The hamsters were kept in a permanently dark room and students tracked the hours their hamster spent sleeping vs. active. If recorded meticulously enough, the so-called actogram would show a beautiful pattern, with every hamster falling asleep and jumping onto the hamster wheel after the same amount of time has passed each day. The pattern repeated itself every 23.5hrs, the approximate length of a day.

Bob's Actogram

(Wondering why no animal has a perfect 24hr cycle? This is theorized to happen so the feeding times are shifted between individuals, and there’s no mass gathering at the waterholes, and feeding grounds. Humans on the other hands make schedules and dates, once more showing how strange we are in our unwillingness to give in to the animal in us.) 

Menaker had never come across a hamster unwilling to fit into the 24hr rhythm. Till one day, according to academic legend, one of his students asked him whether he could have a new animal – his ones was “broken”. Instead of fitting into the usual 24hr cycle, this male had a shortened cycle of only 20hrs. It was acting like it was permanently jetlagged! The student refused to work any further with such a freak of nature, seeing as it would only add more work to his protocol by having to explain the findings. Unlike his (disappointing) student, Menaker did not think the hamster was broken. This was the first opportunity to discover the inner clock of the body!

Menaker could have simply cut up the hamster in search of these cells. But thanks to a decent amount of forethought, he did not get straight to the operation table for the dissection. Instead, he started breeding the hamster. In accordance with Mendelian inheritance, he managed to breed:

  • 20hr, homozygous (both chromosomes carry the same circadian rhythm altering mutation) and
  • 22hr, heterozygous (one chromosome carries the mutation, the other the wild type) offspring in the second generation after the original jetlagged hamster.

So he had enough 20hr hamsters to study now. The next thing to contemplate was: How does our environment make contact with the mystery cells to tell them what’s happening out in the world? Sunlight is one way to tell us it’s daytime – and time to be active. Sunlight helps us to wake up. Just think of the terrible winter months, especially if you live in northern Europe. Nothing is harder than getting up when the sun is still missing from the pitch-black sky in the early morning. Temperature is another good influence on our mystery cells, just as a regular meal schedule helps us get back on track after a red-eye flight. But the latter two fluctuate greatly in the wild. Meal schedules change for animals, and temperatures can drop and rise throughout the day with weather changes. Sunlight on the other hand is a very potent effector. Think of those times you use your cell phone at night. The soft glow can have huge effects on your sleeping pattern.

So if we choose sunlight as our effector of the circadian rhythm (as Menaker did), what cells should we focus on next? Most of you will place your bets on the eyes. Yet, experiments with animals born blind will show you that they’re still very capable of keeping the time of the day, despite not being able to see. We must therefore assume that the receptors responsible for vision, the rods and cones, are not involved in setting our inner clocks. But don’t pay off the bet you placed on the eyes just yet! There is a third type of receptor, the retinal ganglion cells. They are light-sensitive and intact in blind animals. Could this be the inner clock? Unfortunately not. These receptors do not produce any proteins necessary to keep the time. (Now’s the time to pay off your bet.)

Menaker kept thinking. Maybe the eyes are just portals to our master clock cells? If they are, then the next place to check is the brain. Menaker chose to focus on areas in it linked to the eyes and tried to disrupt the circadian rhythm of his hamsters. And indeed, when Menaker (how do I put this in a way that none of you will feel queasy…) removed a certain area of the hypothalamus, the hamsters could no longer fit into any circadian rhythm! This area has been dubbed the SUPRACHIASMATIC NUCLEUS. (Essentially, this means “a bunch of cells located above the crossing of the nerves connected to the eyes (optic chiasm)”.) Big words for such a small part of the brain, so we’ll stick with the abbreviation: SCN. The cells in the SCN are the clock makers, and exposure to light sets off a beautiful interplay between production and break-down of a number of, thankfully pronounceable, proteins: Period (PER) and Cryptochrome (CRY). The pathway in a few sentences: In the brain, PER and CRY are produced and bind to one another. As a team, they can bind to their own gene and prevent their own production when a maximum concentration threshold has been breached. The body breaks down the proteins and the minimum concentration threshold is crossed. This is the signal for the pattern to start again – approximately 24hrs later.

Now, jetlag is painful, not only for the one going through it, but also for everyone who suddenly has to put up with a grumpy loved one shuffling through the apartment at ungodly hours and falling asleep during daytime adventures. Unfortunately, despite understanding the biochemical basis, there’s still little we can do to easily jump through time. It takes approximately a day for every hour for your PER and CRY cycle to shift. But take comfort, as I have, in your newfound abilities to watch the sun rise in the mornings without the struggle to get out of bed. There’s no better way to look forward to new discoveries and adventures, to celebrate the new day that awaits. Serendipity might just make it your best one yet.

cropped-sunsetbot2.jpg

References

A mutation of the circadian system in golden hamsters. Ralph, Menaker (1988)

Genetics of circadian rhythms in mammalian model organisms. Lowrey, Takashi (2011)

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3 thoughts on “Inner Clocks and Jetlagged Hamsters

  1. This is definitely one of your best blogs I have read so far. The story really is quite intriguing. But you didn’t mention how light exposure comes into play with this oscillatory process of protein-production. Does it lower (or raise?) the concentration-threshold, thereby making me post to you at 01.00 AM?

    Kind regards,
    Peter-Max

    Like

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