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Rosemary Braun, Northwestern University
(THE CONVERSATION) In life, timing is everything.
The internal clock of your body – the circadian rhythm – regulates an enormous variety of processes: when you sleep and wake up, when you are hungry, when you are most productive. Given the tangible effect on so much of our lives, it is not surprising that this also has a huge impact on our health. Researchers have linked the health of circadian to the risk of diabetes, cardiovascular disease and neurodegeneration. It is also known that the timing of meals and medicines can affect how they are metabolized.
The ability to measure a person's internal clock is vital for improving health and personalizing medicines. It can be used to predict who is at risk of becoming ill and to follow the recovery from injuries. It can also be used to time the delivery of chemotherapy and blood pressure and other medications, so that they have the optimal effect at lower doses, minimizing the risk of side effects.
However, accurate reading of the internal clock remains a major challenge in the sleep and health of children. The current approach requires taking blood samples every hour of melatonin – the hormone that regulates sleep – during the day and night, which is expensive and extremely stressful for the patient. This makes it impossible to include in routine clinical evaluations.
My colleagues and I wanted to obtain accurate measurements of the internal time without the need for stressful series samples. I am a computational biologist with a passion for the use of mathematical and computational algorithms to understand complex data. My co-workers, Phyllis Zee and Ravi Allada, are world-renowned experts in sleep medicine and circadian biology. Together we worked on a simple blood test to read someone's internal clock.
Listening to the music of cells
The circadian rhythm is present in every cell of your body, guided by the central clock located in the suprachiasmatic core area of the brain. Just like the secondary clocks in an old factory, these so-called "peripheral" clocks are synchronized with the master clock in your brain, but also stabbed themselves – even in Petri dishes!
Your cells keep time through a network of core clock genes interacting in a feedback loop: when a gene is switched on, its activity causes another molecule to roll it back and this competition results in an ebb and flow of gene activation within a 24 hour cycle . These genes in turn regulate the activity of other genes that also oscillate during the course of the day. This mechanism of periodic gene activation orchestrates biological processes across cells and tissues, allowing them to take place synchronously at specific times of the day.
The discovery of the core bell genes is so fundamental to our understanding of how biological functions are orchestrated, that it was recognized by the Nobel Committee last year. Jeffrey C. Hall, Michael Rosbash and Michael W. Young have together won the Nobel Prize in Physiology or Medicine 2017 for their discoveries of molecular mechanisms that govern the circadian rhythm. Other researchers have noted that no less than 40 percent of all other genes respond to the circadian rhythm, which also changes their activity during the day.
This gave us an idea: perhaps we can use the activity levels of a series of genes in the blood to derive one's internal time-the time your body thinks it is, no matter what the clock says on the wall. Many of us have had the experience of feeling "out of sync" with our environment – as if they were feeling at 5 a.m. in the morning, although our alarm system indicated that it is already 7 o'clock. 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 what time it is for you personally. Knowing what profound influence a person's clock can have on biology and health, we were inspired to try to measure the activity of genes to measure the exact internal time in an individual's body. We developed TimeSignature: an advanced calculation algorithm that could measure an individual's internal clock based on gene expression using two simple blood samples.
Design a robust test
To achieve our goals, TimeSignature had to be easy (measuring a minimal number of genes in just a few blood samples), very accurate and – more importantly – robust. That is to say, it should be an equally accurate measure of your intrinsic physiological time, whether you have had a good night's sleep, recently returned from a foreign vacation, or woke up all night with a new baby. And it had to work not only in our laboratories, but also in laboratories throughout the country and around the world.
In order to develop the biomarker for gene signs, we collected tens of thousands of measurements from a group of healthy adult volunteers every two hours. These measurements indicated how active each gene was in each person's blood during the course of 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 search through this data in a computational way to select a small set of biomarkers that would reveal the time of day. A set of 41 genes was identified as being the best markers.
Surprisingly, not all TimeSignature genes are part of the well-known "core clock" circuit – many of them are genes for other biological functions, such as your immune system, that are driven by the clock to fluctuate throughout the day. This underlines the importance of circadian control – the effect on other biological processes is so strong that we can use these processes to monitor the clock!
Using data from a small subgroup of patients from one of the public studies, we have trained the TimeSignature machine to predict the time based on the activity of those 41 genes. (Data from the other patients were kept separate to test our method.) Based on the training data, TimeSignature & # 39; learn & # 39; how different patterns of gene activity correlate with different times of the day. After learning these patterns, TimeSignature can then analyze the activity of these genes in combination to calculate the time that your body thinks it is. For example, although it may be outside of 7:00 am, the gene activity in your blood corresponds to the pattern of 5:00, indicating that it is still in your morning at 5:00 a.m. body.
We then tested our TimeSignature algorithm by applying it to the remaining data and demonstrated that it was very accurate: we were able to derive the internal time of a person within 1.5 hours. We have also shown that our algorithm works on data collected in different laboratories around the world, which suggests that it can be easily adopted. We were also able to demonstrate that our TimeSignature test could detect the intrinsic circadian rhythm of a person with high accuracy, even if they had lack of sleep or had jet lag.
Harmonization of health with TimeSignature
By making circadian rhythms simple to measure, TimeSignature opens up a wide range of possibilities to integrate time into personalized medicine. Although the importance of circadian rhythms for health has been noted, we have only scratched the surface when it comes to understanding how they work. With TimeSignature, researchers can now easily record very accurate measurements of internal time in their study, and record this vital measurement with only two simple blood samples. TimeSignature allows scientists to investigate how the physiological clock affects the risk of different diseases, the effectiveness of new drugs, the best time to study or practice and more.
Of course, a lot of work still needs to be done. Although we know that circadian alignment is a risk factor for diseases, we do not yet know how much alignment is bad for you. TimeSignature allows further research to quantify the precise relationships between circadian rhythms and disease. By comparing the TimeSignatures of people with and without disease, we can investigate how a disturbed clock correlates with disease and predicts who is at risk.
On the way, we suggest that TimeSignature goes to your doctor's office, where your circadian health can be checked just as quickly, easily and accurately as a cholesterol test. For example, many medicines have optimal dosing times, but the best time for you to take your blood pressure medication or chemotherapy may differ from someone else.
Previously, there was no clinically feasible way to measure this, but TimeSignature allows your doctor to perform a simple blood test, analyze the activity of 41 genes, and recommend the time that would give you the most effective benefits. offer. We also know that circadian alignment – when the clock of your body is not in line with the external time – is a treatable risk factor for cognitive decline; with TimeSignature we could predict who is at risk and possibly intervene to align their clocks.
This article has been republished in The Conversation under a Creative Commons license. Read the original article here: http://theconversation.com/simple-blood-test-could-read-peoples-internal-clock-102878.