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In life, timing is everything.
Your body's internal clock – the circadian rhythm – regulates a wide variety of processes: when you sleep and wake up, when you're hungry, when you're most productive. Given its palpable effect over a large part of our lives, it is not surprising that this has a huge impact on our health. Researchers have linked circadian health to the risk of diabetes, cardiovascular disease and neurodegeneration. It is also known that the timing of meals and medications can influence their metabolism.
The ability to measure the internal clock is essential for improving health and personalizing medicine. It could be used to predict who is at risk for illness and to follow recovery from injury. It can also be used to time the administration of chemotherapy and blood pressure and other medications so that they have the optimal effect at lower doses, thus minimizing the risk side effects.
However, reading its internal clock remains a major challenge for sleep and circadian health. The current approach requires taking hourly samples of blood melatonin – the hormone that controls sleep – day and night, which is expensive and extremely cumbersome for the patient. This makes integration impossible in routine clinical evaluations.
My colleagues and I wanted to get accurate measurements of internal time without having to resort to tedious serial sampling. I am a computer biologist passionate about using mathematical and computer algorithms to make sense of complex data. My collaborators, Phyllis Zee and Ravi Allada, are world-renowned experts in sleep medicine and circadian biology. Working together, we designed a simple blood test to read a person's internal clock.
Listen to cell music
The circadian rhythm is present in every cell of your body, guided by the central clock that resides in the region of the suprachiasmatic nucleus of the brain. Like the secondary clocks of an old factory, these so-called "peripheral" clocks are synchronized to the master clock of your brain, but they also advance alone, even in Petri dishes!
Your cells keep the time to cross a network of clock genes that interact in a feedback loop: when one gene activates, its activity causes the return of another molecule, which which causes a flow and a reflux of genetic activation – cycle time. These genes in turn regulate the activity of other genes, which also oscillate during the day. This mechanism of periodic gene activation orchestrates biological processes through cells and tissues, allowing them to proceed synchronously at specific times of the day.
The discovery of the main genes of the clock is so fundamental to understand how the biological functions were orchestrated last year by the Nobel Committee. Jeffrey C. Hall, Michael Rosbash and Michael W. Young together won the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling circadian rhythm". Other researchers have noted that up to 40% of other genes respond to the circadian rhythm, also changing their activity during the day.
This gave us an idea: maybe we could use the activity levels of a set of genes in the blood to infer the internal time of a person – the time that your body thinks , regardless of what the wall clock says. Many of us felt we were feeling "out of sync" with our environment – feeling like at 5 pm, even though our alarm lingers at 7 am. This may be due to the fact that our activities are not synchronized with our internal clock – the clock on the wall is not always a good indication of the time for you personally. Knowing what profound impact the internal clock can have on biology and health, we were inspired to try to evaluate gene activity in order to measure the precise internal time in an individual's body. We developed TimeSignature: a sophisticated calculation algorithm that measures a person's internal clock from gene expression using two simple blood tests.
Design a robust test
To achieve our goals, TimeSignature had to be easy (measure a minimal number of genes in a few blood tests), very accurate and, above all, robust. That is, it should provide as accurate a measure as possible of your intrinsic physiological time, whether you have had a good night's sleep, recently returned from vacation abroad or spent the night with a new baby. And this should work not only in our laboratories but also in the laboratories of the country and the world.
To develop the biomarker of the genetic signature, we collected tens of thousands of measurements every two hours from a group of healthy adult volunteers. These measurements indicated how each gene was active in each person's blood during the day. We also used published data from three other studies that had collected similar measurements. We then developed a new machine learning algorithm, called TimeSignature, that could computerically search for this data to extract a small set of biomarkers revealing the time of day. A set of 41 genes has been identified as the best marker.
Surprisingly, not all TimeSignature genes are part of the known core clock circuit – many of them are genes of other biological functions, such as your immune system, that fluctuate throughout the day. This highlights how important circadian control is – its effect on other biological processes is so strong that we can use these processes to monitor the clock!
Using data from a small subset of patients from one of the public studies, we trained the TimeSignature machine to predict the time of day according to the time of day. 39 activity of these 41 genes. (Data from other patients were kept separately to test our method.) Based on the training data, TimeSignature was able to "learn" the correlation between different patterns of gene activity and different times of the day. Having learned these patterns, TimeSignature can then analyze the activity of these genes in combination to determine how long your body thinks. For example, although it may be at 7 am outside, the activity of the gene in your blood could match the 5 o'clock pattern, indicating that it is still 5 am in your body .
We then tested our TimeSignature algorithm by applying it to the remaining data, and we demonstrated that it was very accurate: we were able to deduce a person's internal time in an hour and a half. We have also demonstrated that our algorithm works on data collected in different labs around the world, suggesting that it could be easily adopted. We were also able to demonstrate that our TimeSignature test could detect a person's intrinsic circadian rhythm with great accuracy, even in the case of lack of sleep or delay.
Harmonize health with TimeSignature
By making circadian rhythms easy to measure, TimeSignature offers a wide range of possibilities for integrating time into personalized medicine. Although the importance of circadian rhythms for health has been noted, we have really only scratched the surface when it comes to understanding how they work. With TimeSignature, researchers can now easily include extremely accurate measurements of internal time in their studies, incorporating this vital measure with the aid of two simple blood tests. TimeSignature allows scientists to study how the physiological clock influences the risk of various diseases, the effectiveness of new drugs, the best times to study or exercise, and so on.
Of course, there is still a lot of work to be done. Although we know that circadian misalignment is a risk factor for disease, we do not yet know how bad the misalignment is for you. TimeSignature allows further research to quantify the precise relationships between circadian rhythms and disease. By comparing TimeSignatures of people with and without illness, we can study how a disturbed clock correlates with illness and predict who is at risk.
Later, we anticipate that TimeSignature will make its entrance into your doctor's office, where your circadian health could be monitored as quickly, easily, and accurately as a cholesterol test. Many medications, for example, have optimal times for dosing, but the best time to take your blood pressure medication or chemotherapy may be different from that of someone else.
Previously, there was no clinically feasible way to measure it, but TimeSignature allows your doctor to do a simple blood test, analyze the activity of 41 genes and recommend the time that would get you the most effective benefits. We also know that circadian misalignment – when your body's clock is out of sync with external time – is a treatable risk factor for cognitive decline; With TimeSignature, we can predict who is at risk and possibly intervene to align their clocks.
SOURCE: The conversation
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