Recent discoveries around the internal clock are opening up the horizons of medicine, cancer treatments in mind. There is the time that is displayed on the wrist or on a smartphone. And there is the one, as secret as it is demanding, that makes your body pulsate. In the 1980s, Israeli researchers discovered the functioning of this internal clock located in the hypothalamus, a small cerebral gland. "This time giver reacts to light, via two centers of perception located behind our eyes:the suprachiasmatic nuclei (SCN)", describes François Duforez, sports and sleep doctor. "This precision mechanics organizes metabolic activity on a cycle of about 24 hours called circadian, dominated by the alternation day/dark".
It dictates the rhythm of the organs, the heart rate, the variations of hormonal secretions, the temperature or the blood pressure... without forgetting the periods of wakefulness and sleep. Medicine has already mastered the influence of light on this precision mechanics. Thus the applications of light therapy relieve the daily lives of people subjected to the winter blues – i.e. 5% of French people, to successive time differences, or even to work in staggered hours. But recently, chronobiological rhythms are at the center of new research, that of chronomedicine; or how to provide better care by relying on the patient's internal clock.
Video of the day:The shift dates back to 2017, when the three American researchers Jeffrey Hall, Michael Rosbach and Michael Young received the Nobel Prize for Medicine for their work on the molecular mechanisms of the circadian cell clock. "Showing that each organ but also each cell has its own clock has revolutionized the entire medical chronobiological approach", declares Sylvie Giacchetti, hospital practitioner at the Sénopole of Saint Louis hospital at the APHP, at the microphone of France Culture. The award boosts the recognition of this emerging scientific sector which immediately attracts new researchers.
Studies around chronotherapy are more than ever on the front of the stage. The role of chronobiological disorders in the triggering of certain diseases, cancers in the lead, is increasingly studied. "Large studies have thus demonstrated an increased risk of breast cancer among nurses practicing shift work (at night)", evokes Sylvie Giacchetti. An American team has already demonstrated the benefits of twice-daily light exposure on patients with Parkinson's disease. Above all, the researchers show that adjusting therapies, especially in oncology, according to the time of day or night significantly reduces the toxicity of certain drug treatments.
"It is a question of reducing the side effects of medical treatments while increasing their effectiveness by modulating the schedules of drug intake; this is particularly relevant for anti-cancer protocols, which are often burdensome for patients, starting with chemotherapy" , summarizes Annabelle Ballesta, INSERM researcher in personalized medicine and chronotherapy of cancers at the Paul Brousse hospital, in Villejuif. "Located in the brain, the suprachiasmatic nuclei generate rhythms throughout the body, down to the level of peripheral tissues. Each cell in our body thus has its circadian clock, synchronized by a kind of central pacemaker", describes the researcher.
On the contrary, cancer cells escape circadian control, are not synchronized with each other and sometimes do not have a functional circadian molecular clock. “We exploit this temporal difference in the chronotherapy of cancers”, explains the expert. Since chemotherapy molecules are generally the cause of severe toxicities, specifying the time of administration of the drug reduces these harmful effects, which makes it possible to increase the dose and therefore the effectiveness of the treatment. "In concrete terms, the drug is given when the healthy cells are the least sensitive; the cancerous cells having no rhythm, they will then be more sensitive to the treatment than the healthy cells", analyzes Annabelle Ballesta.
Today, chronotherapy protocols are currently applied at the Paul Brousse hospital in Villejuif. To determine the ideal time of administration of a drug, it is necessary to study the circadian rhythms of the targeted area. For example the part affected by the tumour; or the intestine, cancer patients suffering from severe diarrhea in the wake of chemotherapy.
"Our mission is to study these organs and metabolic circuits to determine when the drug will induce the least possible damage; for this we need to personalize the therapies because each person has their own clock; major differences are also readable depending on the genre”, explains Annabelle Ballesta. In other words, and this is new, the body of a man or a woman reacts very differently to treatments. "We have just carried out tests with the drug Irinotecan, prescribed in colorectal and pancreatic cancers. Result:the hour of least toxicity is early in the morning (between 5 and 9 a.m.) for humans, and around 5 p.m. for women", illustrates the researcher.
The results in chronotherapy have also been proven on the administration of anti-inflammatories for rheumatoid diseases, such as osteoarthritis. To be most effective, the drug must be active very early in the morning, when the patient feels the most pain. Drugs have therefore been developed to be taken late at night, for a release of active ingredients during the night in order to alleviate the suffering on waking.
At the same time, the discipline is making its debut in cardiovascular medicine:the Lille University Hospital has shown that the side effects after heart surgery which involves disconnecting and then reconnecting the heart were greater if the operation takes place in the morning than afternoon (15% of cases of complication against 8%). Key element to integrate into the equation:the patient's chronotype. "There are morning chronotypes:the biological clock of these people is shorter than the terrestrial clock. Those of the evening, on the contrary, are rather late in phase because their internal clock exceeds 24 hours", explains François Duforez.
The chronotype then shifts the metabolic rhythms and therefore the optimal rules of administration. Measuring the latter is a major current challenge. To determine circadian rhythms at an individual level, the patient must be equipped with a sensor, via a watch for example, which will measure activity, temperature, heart rate, etc. "The second challenge will be to better understand the chronobiological mechanism at a molecular level, at the level of the cell". This part of research goes beyond chronotherapy because it involves multidisciplinary studies, particularly at the in vitro level but also mathematical. The idea is to develop techniques that will make it possible to reliably measure the rhythms of each patient in order to predict the optimal schedules for drug or surgical treatments. The future is open!
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