Metabolic
Resetting the biological clock by flipping a switch
The biological clock is present in almost all cells of an organism. With increasing evidence that clocks in certain organs may be out of sync, these clocks need to be examined and reset locally. Scientists from the Netherlands and Japan introduced a light-controlled on / off switch for a kinase inhibitor that affects clock function. This gives them control over the biological clock in cultured cells and explanted tissue. They publish their results today (May 26, 2021) in Nature Communications.
Life on earth developed in a 24-hour cycle. of light and dark, hot and cold. “This synchronizes our cells to these 24-hour oscillations,” says Wiktor Szymanski, Professor of Radiological Chemistry at the University Medical Center Groningen. Our circadian clock is regulated by a central control in the suprachiasmatic nucleus, a region in the brain just above the optic nerve, but all of our cells contain their own clock. These clocks consist of a vibration in the production and breakdown of certain proteins.
light switch
“It is becoming increasingly clear that these clocks in organs or tissues can be disrupted, which can lead to disease,” adds first author Dušan Kolarski, a doctoral student from the group led by Ben Feringa, professor of organic chemistry. And of course, we all know the jet lag caused by traveling across time zones or issues caused by switching to or from daylight saving time. “We know very little about how our cells coordinate these vibrations or how they affect the body when, for example, a kidney is out of phase with the rest of the body,” he adds.
To study these effects, it would be useful to have a drug that affects the clocks and that can be activated locally. The latter has already been done by Szymanski and Feringa’s groups. They created various compounds like antibiotics or cancer drugs that could be turned on and off with light. Previously, the circadian biologist Tsuyoshi Hirota, associate professor at the Institute for Transformative Biomolecules at Nagoya University, Japan, developed a kinase inhibitor, longdaysin, that slows the circadian clock down to a cycle that lasts up to 48 hours. Kolarski equipped this Longdaysin with a light switch with which he could activate or deactivate the connection with violet or green light.
Time zone
This customization took several years to develop, but the result was well worth the effort. “It was a real scientific tour de force and a fine example of interdisciplinary collaboration,” adds Feringa. Together with their Japanese colleagues at Nagoya University, the scientists from the University of Groningen showed how the cycle of cultured cells was extended from 24 to 28 hours by treatment with the Longdaysin derivative. Deactivating with green light brought the cycle back to just over 25 hours and then reactivating with purple light brought it back to 28 hours.
“We also used it in tissue sections from the suprachiasmatic nucleus of the mouse,” says Kolarski. “The oscillations slowed down to a 26-hour cycle after several days of treatment with the Longdaysin derivative and returned to a 24-hour cycle after deactivation with the green light.”
“This reversible regulation offers a new approach to analyzing the organization of the clock in each cell at the tissue level in order to gain a deeper understanding of the complex circadian clock system,” adds Hirota.
The scientists also adjusted the phase of the cycles in cultured cells: activating the Longdaysin derivative for three days, followed by deactivation, caused the 24-hour cycle to be shifted by up to six hours. It is as if the cells were synchronized with a different time zone. The experiments are proof of the principle and allow scientists to study the circadian clock in much more detail. The next step would be to use Longdaysin on animals. Kolarski: “The original Longdaysin without a switch has already been used with zebrafish. We’d love to test it on mice. The aim is not to fix jet lag, but to study the effects of Longdaysin on physiology. “
organs
A light-activated drug like Longdaysin is likely only used to treat serious medical conditions. “We can actually reach some organs with light, for example with an endoscope. The gastrointestinal and respiratory tracts are easily accessible, while other tissues may require small incisions to insert optical fibers, ”comments Szymanski. There are also several new ways to generate light in organs or tissues through techniques such as bioluminescence or sonoluminescence. Although these light levels are still several orders of magnitude below what we need to operate a switch. We will work hard to increase sensitivity in the years to come, emphasize both Szymanski and Feringa. Kolarski adds: “We have now opened a new field of study. All of this will ultimately enable us to locally disrupt or repair the circadian vibrations. “
Simple scientific summary
The cells in our body follow a 24-hour cycle, the circadian clock. Disturbances in this cycle, for example through night shifts, can lead to illness. In recent years it has been shown that the clock in individual organs or tissues can be disturbed. In order to study and possibly cure problems with the clocks in our cells, Dutch and Japanese scientists have developed a compound that extends the 24-hour cycle and can be activated or deactivated with light. They showed that it is possible to convert the 24-hour cycle in cells or tissues into a 28-hour cycle by activating the compound. After deactivation, the cells and tissues returned to a nearly normal cycle. The compound can be used to study the clocks in our cells and, ultimately, can be used to treat diseases caused by a malfunctioning clock.
Reference: “Reversible modulation of circadian time with chronophotopharmacology” by reference: Dušan Kolarski, Carla Miró Vinyals, Akiko Sugiyama, Ashutosh Srivastava, Daisuke Ono, Yoshiko Nagai, Mui Iida, Kenichiro Itami, Florence Tama, Wiktor Szymanski, Tsuyoshi Hirota Feringa, 26 May 2021, Nature Communications.
DOI: 10.1038 / s41467-021-23301-x