Your body has a clock—and thanks to the travails of modern life, that clock may not line up with the timing of the outside world. These circadian rhythms drive physical processes both big and small and can influence everything from how well we think to how—and when—we gain weight. That means a difference between internal and external time can really mess people up.
As you might imagine, researchers are keen to understand more about how this clock works. But it’s difficult to measure different people’s clocks. The conventional way of doing it requires numerous blood samples, taken over a number of hours, to measure changes in melatonin. “It’s expensive and burdensome for the patient,” says Northwestern University computational biologist Rosemary Braun. But understanding a particular person’s specific internal time allows for things like more effective drug delivery because the human body works differently at different times of day.
Braun is the first author on a new paper outlining a process that takes just two blood samples and then uses an algorithm called TimeSignature to figure out what time it is inside the body. The process is the most straightforward test yet developed, and the most generalizable. To create this test, researchers trained the algorithm to look for chemical evidence of about 40 specific genes in the blood samples. They picked those 40 by analyzing a much larger dataset and finding the ones that express at specific times.
According to the research, the algorithm works regardless of whether the patient is sick or well. That’s significant because gene expression—the way your genes activate, prompting the production of chemicals and helping your body to function—is changed by things as simple as how much sleep you get.
Part of the reason this method works is that it looks beyond the (relatively) well-understood macroscopic processes like sleeping and waking that can be attributed to the body’s clock, says Braun. The clock “also controls biological processes right down to the cellular level,” she says. Between 40 and 50 percent of our genes respond to a person’s body clock. “Knowing that so many genes were responsive to the circadian clock gave us the idea of looking for gene activity patterns in the blood that might correlate with what time of day it is,” Braun says. Gene activity in the blood shows up as chemicals. They measured for about 20,000 different genes, she says, “and then we trained a computer to learn which genes were the most predictive of time and how to combine those markers in order to get a very accurate assessment of physiological time.“
All the body’s cells have tiny internal clocks that are regulated by a cluster of things dictated by part of the hypothalamus, including melatonin. That’s why measuring melatonin levels over many hours can provide an accurate picture of the body’s internal time, as the current clinical test does. By looking at the chemical evidence of gene expression shaped by melatonin levels, this new test essentially flips the old test on its head, while drawing in other factors it didn’t previously account for. It’s also predictive, which means it can extrapolate from existing data and requires fewer data points. Northwestern University has filed for a patent on the blood test, but the algorithm and software will be publically available.
The researchers found something unexpected—the genes that are the best predictors of body clock aren’t all “what we could call the core clock genes,” Braun says. “A lot of them are genes that are related to other biological processes, but they're regulated by the clock. They're regulated so tightly by the clock that observing them becomes a good marker for the clock itself.”