Tag Archives: circadian rhythm

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It’s About Time

‘What then is time? If no one asks me, I know what it is. If I wish to explain it to him who asks, I do not know.’ So wrote Saint Augustine, bishop of Hippo in North Africa, more than fifteen hundred years ago. And we’re still confused… Okay, I’m confused.

When considered philosophically, you’d think it would be a relatively simple concept: I exist right now: the Present; I remember what happened to me: the Past; I don’t know what will happen to me: the Future. That is Time. It is divided into separate Magisteria like scenes through the window of a moving train. And yet… and yet the divisions seem so arbitrary. So evanescent. It’s almost as if Time were merely an all-purpose synonym for Change. A generic label.

But things happen in time, our bodies being no exceptions, so it’s difficult to ignore. We have come to prioritize those happenings as constituting Time. The intervals between events have gradually become divested of significance, although whether it is the interval, or the event that is prime could be argued -much as whether the placement of a comma in a sentence contributes almost as much to the meaning to be conveyed as the words themselves. And yet, is it really all contingent…?

Are habits -those things we do almost without thought- or the endless train of happenings the commas? Is it actually in the intervals between things where we live? Do we inhabit the interstices, and merely mark their boundaries by events -rely on things that happen in order to count? Do we live between the nodes or does reality only exist for me when stuff happens, when I am aware of what I am doing? And if so, then what about when I’m not aware? What happens to Time then? Do you see why I am confused?

And, at the risk of sounding too Cartesian, is the reality my body inhabits different from the awareness my mind tells me about? Bodily existence seems to have been issued with different rules because it is far more contingent than my mind. Too needy. Too ad hoc, and less spontaneous. It seems overly pulled by evolution and ontogeny, unable to explore new things. It straddles the intervals like a bridge. It is a scaffolded entity, constantly in a state of repair.

No, Time, for a body at least, was always thought to be continuous. Contiguity of events allows restoration and medicine discovered this. It started on its quest to heal the body, even if the mind was not always in synchrony and did not understand. But it assumed that mind was only a by-product of body. It is… isn’t it…?

At any rate, something that has often puzzled me is the difference in prescription instructions for various medications. Of course some drugs are relatively short-acting, and need to be taken frequently, say, Q6H (every six hours), or perhaps they are more potent and require a smaller, but spaced out administration, say, Q8H. That seems fairly obvious, so instructions as to how much and how frequently to take them would therefore make sense.

But suppose the directions are to take them QID (four times per day) or even TID (three times per day)? By comparison, that seems almost sloppy, doesn’t it? I mean, what is the difference…? And how much variation is permissible between the timing of every eight hours, and three times per day? What impact would, for example, a two hour difference -or even more- have on the medication efficacy? This is not meant as a criticism, but merely an exploration of time in the administration of a treatment.

And yet, even a more precise prescription of the interval does not usually state a specific time for its consumption like, say, 8 PM. Given that our bodies (and hence probably our metabolism) are subject to a circadian rhythm, I’ve often wondered whether that might make a difference in a medication’s effectiveness. An article in Nature that I ran across addresses that very issue: https://www.nature.com/articles/d41586-018-04600-8?utm

‘The circadian clock is a remarkable system. A central timekeeper in the hypothalamus orchestrates a network of peripheral clocks in nearly every organ and tissue of the body, turning on and off a bevy of genes including some that encode the molecular targets for drugs and the enzymes that break drugs down. These clock genes are particularly important in cancer because they govern cell cycles, cell proliferation, cell death and DNA damage repair — all processes that can go haywire in cancer.’

Until recently, technology was unable to determine the genes involved, let alone the timing of their activation, and so chronotherapy remained on the fringe. But, ‘More than four decades of studies describe how accounting for the body’s cycle of daily rhythms — its circadian clock — can influence responses to medications and procedures for everything from asthma to epileptic seizures. Research suggests that the majority of today’s best-selling drugs, including heartburn medications and treatments for erectile dysfunction, work better when taken at specific times of day.’

Steroid levels, for example, ‘naturally cycle with the circadian clock. In the late 1960s, scientists found that the synthetic corticosteroid methylprednisolone is safer for treating arthritis and asthma if taken in the morning rather than at other times of the day. This is because the feedback loop in the hypothalamus, which controls the release of cortisol, is least vulnerable to inhibition in the morning.’ Other factors such as age and gender also seem to be important in circadicity. So is the inconvenience of the times when the appropriate genes might best be manipulated. Not only that, but ‘practical biomarkers are needed to help clinicians identify optimal times for treatment.’

There are many variables to account for, but clearly there is a growing appreciation of Time in understanding the body’s underlying physiology. There is a need to adjust not only the treatment, but also its provision in harmony with individually derived schedules that are often by no means intuitive or convenient. As if, by finding each body’s unique variations on the theme of circadian rhythm, we discover the hidden melody playing deep within.

Maybe Rabindranath Tagore, the Bengali polymath who won the Nobel prize in Literature in 1913, was not so far afield after all: Let your life lightly dance on the edges of Time like dew on the tip of a leaf.

I’d like to think we all dance in Time…

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The Body’s Clock

Scientists –well, all of us- have been suspicious about the health risks of shift work for a long time now. Perhaps there is a reason buried somewhere in our genes that suggests night is for sleeping and daytime for working. Originally, no doubt, it was because it was difficult to see things in the dark and lighting, even when it became available, wasn’t very good.

But there is another reason: the Circadian Rhythm (from the Latin circa –around, and dies –day) which is often defined as physical, mental and behavioral changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. The body clock, in other words. And there’s the clue: light and darkness. These are not just elements in our environment that we have come to expect, they actually have a biological meaning for us although this is, to a certain extent, entrainable. Malleable. As Wikipedia (sorry!) puts it: The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment. The external stimulus used to entrain a rhythm is called the Zeitgeber, or “time giver”. But it can take a while to adjust –think of jetlag, or sleep disturbance after starting a new shift at a different time.

The body can adapt to many things, no doubt; the problems seem to arise when the pattern keeps changing. As folk wisdom attests, we are inherently creatures of habit –acquired behaviour patterns that are repeated so frequently they can become almost involuntary. As no less an observer of folkways than Samuel Johnson once said: “The chains of habit are too weak to be felt until they are too strong to be broken.” So one might ask why we –and many other animals- seem prone to develop these routines, these almost unconscious ceremonies. Is it simply a need for predictability? Or is it something deeper, something tied to our evolutionary past..?

In our evolutionary development we obviously experienced disruption of light/dark cycles –they occur as we travel through the seasons- but these are gradual and steadily progressive; shift work –especially rotational shift work- is not. And only recently has it become more obvious that there may be a price to pay. There have been several studies that have looked at this in various ways, but ‘Although epidemiological studies in shift workers and flight attendants have associated chronic circadian rhythm disturbance (CRD) with increased breast cancer risk, causal evidence for this association is lacking’ as the abstract of a paper published in Current Biology noted. I saw this in a July 2015 article in BBC News reporting on a study co-authored by Dr. Kirsten Van Dycke which suggested that the chronic need to re-entrain the circadian rhythm because of changing light/dark cycles can increase the risk for both obesity and breast cancer! http://www.bbc.com/news/health-33569161 Now, admittedly, the study was done on mice who were prone to develop breast cancers anyway, but when the light/dark cycles were switched over a long period of time (‘Mice prone to developing breast cancer had their body clock delayed by 12 hours every week for a year’) they developed them sooner.

Humans are obviously not mice, but it is difficult to control for possible contributing factors in the average human study: ‘Several scenarios have been proposed to contribute to the shift work-cancer connection: (1) internal desynchronization, (2) light at night (resulting in melatonin suppression), (3) sleep disruption, (4) lifestyle disturbances, and (5) decreased vitamin D levels due to lack of sunlight. The confounders inherent in human field studies are less problematic in animal studies, which are therefore a good approach to assess the causal relation between circadian disturbance and cancer.’ http://www.cell.com/current-biology/abstract/S0960-9822(15)00677-6

And the conclusion from this study? ‘Animals exposed to the weekly LD [light/dark] inversions showed a decrease in tumor suppression. In addition, these animals showed an increase in body weight. Importantly, this study provides the first experimental proof that CRD [Circadian Rhythm Disturbance] increases breast cancer development. Finally, our data suggest internal desynchronization and sleep disturbance as mechanisms linking shift work with cancer development and obesity’.

This is worrisome, to say the least. One could certainly argue that a woman with an increased risk for breast cancer –say a heditarily aquired BRCA1/2 mutation- would be best to avoid jobs involving chronic irregular body clock disturbance such as flight attendants, commercial pilots, and so on. But I’m not sure the risk is confined to that population. What about others –especially if they have additional life-style risks such as smoking, diabetes, alcohol issues?

And what about men? If –as the study suggests- a chronic body clock disruption may cause a decrease in tumour suppression, would that not suggest a similarly increased risk? The disruption also seems to have an additional risk for increased weight gain –obesity. Is the risk for type 2 diabetes therefore also increased? Clearly this is an area requiring much more research -further elucidation of the mechanisms involved and mitigation strategies at the very least. Sleep is so important –regular sleeping patterns…

I can’t help but remember the words of Shakespeare’s Macbeth talking to his wife after he has killed Duncan, the king:

Methought I heard a voice cry, “Sleep no more!

Macbeth does murder sleep”—the innocent sleep,

Sleep that knits up the raveled sleave of care,

The death of each day’s life, sore labor’s bath,

Balm of hurt minds, great nature’s second course,

Chief nourisher in life’s feast.

Art, once again, anticipating Science…