Updating Magic Universe
A Better Remedy for Jet Lag?
The word from the Max-Planck-Institut für biophysikalische Chemie in Göttingen is that the biological clocks associated with different organs in the body adapt to a new time zone at different rates — but the consequent physiological confusion of jet lag can be reduced, at least in mice, by attending to the adrenal glands, on the kidneys.
A pacemaker in the brain’s hypothalamus, a group of cells called the suprachiasmatic nuclei (SCN), is supposed to synchronize all the other circadian [about a day] clocks. But the adrenal clocks are tasked to prevent over-rapid responses to changes in daylight, for example due to storm clouds. When the researchers either switch off the adrenal clocks or manipulate the synthesis of the hormone corticosterone by the adrenal glands, with the help of the drug metyrapone, the mice adapt more quickly to a new simulated time zone.
Most relevant in Magic Universe is the following passage in the story “Biological clocks: molecular machinery that governs life’s routines”.
By the start of the 21st Century the molecular clockwork was becoming plainer. The slow, hard task of taking the 24-hour clock to pieces had fallen primarily to the geneticists. Seymour Benzer of Caltech showed the way the forward, in the 1970s, by looking for mutant fruit flies with defective clocks and abnormal daily behaviour. In 1988 a golden hamster turned up by chance, with a clock with an aberrant 22-hour cycle.
The possibility of a breakthrough arose when Joseph Takahashi of Northwestern University, Illinois, and his colleagues found a mutant mouse in which the clock period was an hour longer than in his relatives. By 1994, Takahashi’s team could report that they had located that animal’s mutant gene on one of the mouse chromosomes. Strenuous work in several laboratories followed up this discovery and identified several more genes involved in the mammalian clock.
Takahashi’s own group pinned down the mutant gene first seen in the golden hamster, and found the same gene in mice and humans. It turned out to code for making a particular protein molecule, an enzyme of the type called a kinase. A Utah team found a defect in the identical enzyme in a hereditary sleep disorder in human patients. And Takahashi was bowled over to find that the kinase also operates in the 24-hour clock of fruit flies. ‘What’s incredible is that the enzyme appears to be doing exactly the same in fly as in hamster,’ he said. ‘So this is a highly conserved system.’
A preliminary overview of the clockwork came from Steven Reppert of Massachusetts General Hospital and his colleagues. They identified proteins that, they suggested, might promote or repress the action of several genes involved in the clock. By 2000 they had, for example, pinpointed a protein called cryptochrome as one such player. It becomes modified by joining forces with another clock protein and returns to the nucleus of the cell where the genes reside. There it switches off the gene that makes cryptochrome itself.
The swinging pendulum again, with molecule A making B which represses A, in a negative feedback loop. Reppert commented in 2002: ‘Now that we have the loops, we’re asking how the time delays are built into the system through the protein modification to get the 24-hour kinetic to the clock.’
Adding a little of the background to the new work, the update can read as follows:
Experimenting with mice, in collaboration with Cheng Chi Lee (then at Baylor), Gregor Eichele of the Max-Planck-Institut für biophysikalische Chemie in Göttingen identified three genes that regulate the circadian clock. In a group of cells in the brain called the suprachiasmatic nuclei (SCN), the timing of their activity follows a 24-hour rhythm. One of them, mper2, is most active around noon. In jet-lag experiments, changing the lighting in the mice’s cages, mper2 remains active at the “old” noon for two days, before gradually resetting to the “new” noon.
In 2010 with colleagues in Göttingen – Silke Kiessling and Henrik Oster – Eichele reported a possible breakthrough in the management of jet lag. While the SCN in the brain is the main coordinator of the biological clocks in other organs of the mammalian body, the timings become uncoordinated in jet lag. The clocks in the adrenal glands on the kidneys exert a restraining influence, which slows down the adaptation. As hormones from the adrenal gland are important, switching off the adrenal clock would be inadvisable, but the time-dependent release of the hormone corticosterone is crucial in enabling the mice to adapt more quickly to the new time. The researchers used the drug metyrapone, which blocks corticosterone production. Silke Kiessling explained:
“If the mice were given metyrapone at the right time, they adapted faster to the disturbed circadian rhythm. While the ‘sleep hormone’ melatonin, which is commonly used to treat jet lag, mainly acts by generating tiredness and is therefore more suitable for use when flying east than west, with metyrapone, the mice’s internal clocks can be turned both forwards and back.”
Max Planck press release (including the Silke Kiessling remark): http://www.mpg.de/english/illustrationsDocumentation/documentation/pressReleases/2010/pressRelease201006242/
Silke Kiessling, Gregor Eichele, Henrik Oster, “A role for adrenal glucocorticoids in the circadian resynchronization during jet lag in mice”, Journal of Clinical Investigation, June 23, 2010
Nigel Calder, Magic Universe, pp. 57-8, Oxford UP 2003