Time-telling tissues

As anyone who has ever suffered from jetlag knows, we are indeed all slaves to the rhythm - in this case our circadian rhythms - or body clocks. And the reason we feel so ghastly when our internal clocks go off kilter is because every cell in our bodies uses time to control what it does and when. Tissues grow and repair themselves at certain times of the day; our metabolism changes dramatically between dawn and dusk. And medicines and vaccines given at one time of day can be much more effective than the same drug administered just hours later. This means that there is enormous potential to improve healthcare - but only if we can reliably tell what time our tissues think it is.

Now Rosemary Braun, from Northwestern University in the US, has developed a way to do this by comparing the activities of a collection of different genes in blood cells. Chris Smith spoke to Rosemary...

Rosemary - You have an internal clock in your body. The signal for it originates in your brain but it orchestrates a wide variety of processes across your body including when you feel sleepy; it regulates your digestion; it regulates your blood pressure to get you ready for the day; it regulates your body temperature to allow you to sleep comfortably at night. And all of these things are coordinated by clocks that exist in each and every cell of your bodies. There’s a master clock in your brain and it synchronizes all of these little tiny cellular clocks.

Chris - Do we know, Rosemary, what the clockwork is inside all these cells that are running these clocks to keep time like that?

Rosemary - Yeah. This is really fascinating. It’s a set of genes that have an activity that varies over the course of the day and they interact with each other in a little circuit that allows them to regulate each other. So one comes up, it pushes another one down, and this push and pull results in an ebb and flow of activity with a 24 hour cycle.

Chris - And what, the brain centre then sets the tone for the rest of the body how?

Rosemary - Your brain secretes hormones that your cells pick up in order to reset their clocks so that they’re right in sync with what your brain is telling them.

Chris - So in theory then, if I were to read one of the clock signals from the end of my little finger it should be telling the same time if all is well as my brain?

Rosemary - Exactly.

Chris - So why does this matter? Why do we need clocks in my finger if I have one in my brain at all?

Rosemary - The reason that this is so important is that you need all of the processes across your body to be orchestrated in sync so that you remain healthy. Given that it controls things ranging from not just sleep to digestion and blood pressure, you can imagine that it has an enormous impact on your health if it’s misaligned in some way. In fact, research has shown that circadian misalignment, when your clock is out of sync with your environment, is tied to diseases ranging from depression to diabetes, heart disease, Alzheimer’s, so having a misaligned clock can really adversely impact your health.

Chris - Is that a part of our clinical practice? So when we go and seek treatments are they aligned with our clock to make sure that we’re doing the right thing at the right time in the body’s clock cycle?

Rosemary - Presently they’re not and that’s what we’re trying to change. We know that it’s incredibly important but right now it’s very difficult to measure it. The current way that people have been measuring people’s internal physiological clocks is by taking samples every hour across the day and night. And you can imagine that’s not really something that most people would want to do, so we set out to develop and easy blood test so that we can monitor people’s circadian health and use that to make treatment decisions.

Chris - When you say it’s a blood test, what are you measuring?

Rosemary - It takes two blood samples: say one in the morning, one in the evening. They can actually be taken at any time of day as long as they’re separated by a few hours, and then we look for the activity of different genes in the blood. So there aren’t just the core clock genes that are responding to the 24 hour rhythm. The clock actually controls a huge number of other genes that sort of move in sync with the clock and those are the markers that we’re looking for in the blood.

Chris - So you take some blood, what do you get blood cells out of the blood and then look in those living blood cells to see what the genes levels are?

Rosemary - Yeah, exactly.

Chris - How many genes do you consider then in order to get a readout like this?

Rosemary - We started out our research by looking at all of the genes that we could measure - that’s about 20 thousand different genes, and we used a pretty sophisticated computational algorithm to try to whittle that down to a manageable amount. And what our algorithms told us was that there is a set of about 41 genes that change over the course of the day, and by looking a the levels of those 41 genes we can pinpoint the time in your body.

Chris - Right. So you literally are saying that we know that when it’s 7 o’clock by my body clock this gene should be doing this and it’s counterpart should be doing this, and because you know what the relationships are across that small cluster of genes you’ve got a reasonably accurate way of predicting my body clock time?

Rosemary - That’s right. And it’s accurate to within about an hour and a half which is good enough to be able to then make treatment decisions based on  it.

Chris - What sort of a difference will it make then?

Rosemary - Drugs have a different effectiveness depending on where they are taken. This is well known for certain blood pressure drugs and chemotherapies that they’re differentially affective at different times of day. But the optimal time for me to take my blood pressure drug might be different from the optimal time for you to take your blood pressure drug. If we can measure the time in your body, we can tell you exactly when the optimal time is for you to take your medicines. That means we could use lower doses, reduce the risk of side effects, and hopefully have more effective treatments.