I’ve just arrived home from 14 hours of flying. The clocks on my phone and laptop have been ticking away the whole time, and it takes a few seconds to reset them to British time. The clocks in my body are more difficult.
We run on a daily 24-hour body clock, which controls everything from our blood pressure to our temperature to how hungry we feel. It runs on proteins rather than gears. Once they’re built, these proteins stop their own manufacture after a slight delay, meaning that their levels rise and fall with a regular rhythm. These timers tick away inside almost all of our cells, and they’re synchronised by a tiny collection of 10,000 neurons at the bottom of our brain. It’s called the suprachiasmatic nucleus (SCN). It’s the master clock. It’s the conductor that keeps the orchestra in sync.
The SCN is also sensitive to light. It gets signals from our eyes, which allows it to synchronise its ticking with the 24-hour cycle of day and night outside. The SCN is what connects the rhythms of our bodies with those of the planet.
But when we travel far and fast, and suddenly land in a new time zone, the SCN becomes misaligned with the environment. It takes time to re-adjust, typically one day for every time zone crossed. In the meantime, our sleep is disrupted and our physiology goes weird. In other words: jet lag.
But at Kyoto University, Yoshiaki Yamaguchi and Toru Suzuki have engineered mice that break this rule. They are, with apologies for the awful word, unjetlaggable. If you change the light in their cages to mimic an 8-hour time difference, they readjust almost immediately. Put them on a red-eye flight from San Francisco to London and they’d be fine.
The secret to their jet lag-resistance lies in a hormone called arginine vasopressin (AVP). Around half of the neurons in the SCN secrete it, and they also detect it using several receptor proteins. Yamaguchi and Suzuki deleted the genes for two of these receptors—V1a and V1b—from their mice. They still make AVP, but they can’t respond to it. By using chemicals that block the same receptors, the team even managed to help normal mice recover from jet lag faster than usual.
But before we start thinking about a “cure” for jet lag, there’s a problem: You can’t deliver drugs directly to the brain, so any pill that blocked AVP receptors would do so across the whole body. And these receptors are found in other organs, like the kidneys. Disrupt them, and you’d affect your blood pressure and your salt levels. Your kidneys might also stop absorbing water and you’d produce urine by the bucket. “The recipient would have to pee like a race horse,” says David Weaver, who studies circadian rhythms at the University of Massachusetts Medical School. “Even with this interesting research, we’re a ways from making a pill that could be swallowed to reset the clock.”
The team’s discovery took a lot of work. They catalogued some 200 genes that are activated in the SCN’s neurons, and deleted them one at a time in mutant mice. They then changed the lights in the animals’ cages so they came on and went off 8 hours earlier or later. They watched for weird behaviour. Of all the rodents, those that lacked both V1a and V1b stood out.
Mice are active at night. When the lights go out, they’re soon up and about. But if you suddenly shift their light cycles forward by 8 hours, it takes longer for them to become active when darkness descends. That’s what mouse jet lag looks like. They recover slowly, just like we do. It takes 8 to 10 days for them to adjust to a leap forward, and 5 to 6 days to adjust to a leap back.
But the team’s mutant mice adjusted almost immediately or, at most, after a day.
Here’s the really surprising bit: the rodent’s clocks still kept time well. They ticked and tocked on the standard daily cycle. Their temperature and behaviour peaked and troughed over 24 hours, as did the activity of genes in their liver, kidneys and brains. “It’s astonishing,” says Hitoshi Okamura, who led the study. “The mutant mice only show abnormal behaviour when they are in the jet lag condition.” They’re like the clocks in my computer and phone—they keep time very well, but they can be reset very easily.
“This is unprecedented,” says Michael Hastings from the University of Cambridge, who studies body clocks. In earlier studies, scientists have tweaked animal clocks so that they quickly adapt to new time zones, but their regular time-keeping duties always suffer as a result. “It always seemed that being a good clock and being very responsive to lighting cycles were mutually incompatible. [These] mice have an SCN that strikes a happy medium.”
How can that be? The team thinks the answer lies in the connections between the neurons of the SCN. Those that produce and respond to AVP all hook up with one another to form tightly synchronised circuits. You can disrupt their clocks with a chemical that stops them from making proteins (remember that proteins are the gears of our body clocks), but once the chemical disappears, they all sync up again. This tight coupling ensures that the master clock keeps on ticking regularly in the face of small environmental changes.
But in the mutant mice, the SCN neurons are more loosely coupled. Disturb their clocks, and they find it hard to synchronise. This doesn’t cause any obvious problems under normal conditions and it actually helps them when challenged by large time differences. Unrestrained by one another, the individual neurons can respond to environmental changes and the entire clock resets very easily.
Beyond jet lag
You don’t want this to happen all the time, but the team managed to temporarily loosen the coupling within the SCNs of normal mice. They treated them with two chemicals that block AVP receptors and showed that they got over jet lag very quickly, albeit less quickly than the mutants that lacked the receptors altogether.
That’s not surprising, says Akhilesh Reddy, a circadian researcher at the University of Cambridge. Growing up without any AVP receptors at all would almost certainly change the connections in the rodents’ brains, producing more dramatic effects than simply blocking the receptors in animals that always had them. Still, the mutants were so resistant to jet lag that duplicating even a fraction of that effect should be helpful to weary travellers.
“The real importance of being able to adjust the clock isn’t for jet lag, which is usually only a nuisance, but for shift-workers,” adds Weaver. “A ‘jet lag pill’ could help shift-workers rapidly adjust their clocks, rather than fighting their biology by trying to stay awake all night and sleep during the day.” This is important because there’s mounting evidence that shift-working is linked to a higher risk of heart disease and some cancers. It poses a big and unappreciated problem for public health—one that might be preventable if scientists can find a way of rapidly reset our body clocks,
Reference: Yamaguchi, Suzuki, Mizoro, Kori, Okada, Chen, Fustin, Yamazaki, Mizuguchi, Zhang, Dong, Tsujimoto, Okuno, Doi & Okamura. 2013. Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag.
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