Chronotherapeutics

We all know that a day lasts 24 hours, which is how long it takes the Earth to rotate once on its axis. What is less well known is that this 24 hour rhythm is much more intrinsic to us than just the movement of a planet - it is part our cells, encoded in our own DNA...

It turns out that almost every cell, be it bacterial, human, in the skin, liver or brain has its own 24 hour "circadian" rhythm. That is, a proportion of the cell's activities occur in cycles of 24 hours. Recent research estimates that around 10% of our genes are regulated in this circadian manner (Akhtar et al. 2002). This rhythm is unaffected by changes in temperature and is hard-wired in to the genetics of the cell, to the extent that an isolated cell will continue with its circadian oscillation even in the absence of external cues.

Why have a circadian rhythm?

There are several proposed reasons as to why the existence of an intrinsic circadian oscillation might have been evolutionarily advantageous. Most of these contain a concept of anticipation. Imagine that you are a plant. In order to maximise resources, plants need to spend as many of the daylight hours as possible photosynthesizing. At night, on the other hand, plants need to utilise the energy that they have stored during the day for growth and repair. A plant lacking a circadian rhythm can only detect day-break (and so the time when you want to start photosynthesizing) by picking up changes in light levels and temperature accompanying sunrise. And because it takes time to detect these changes and then to activate all of the machinery needed, precious photosynthesising time would be lost, compromising growing efficiency.

In contrast, if you are a plant that possesses an intrinsic 24 hour rhythm, then there is no need for you to be subject to the delay in photosynthesis that is seen in your non-circadian counterparts. Instead, you will be able to use your 24 hour rhythm, combined with previous information about night and day length, to predict when the Sun will rise and so when the earliest appropriate time for photosynthesis will be. In other words, you can anticipate. You can then prepare your photosynthetic machinery to be ready for action at this point in the circadian cycle. This way, there is no delay between day-break and the onset of photosynthesis, allowing plants which possess circadian rhythms to photosynthesise for longer than continuously-running plants, and so collect and store more energy. This ultimately confers a competitive advantage on these plants, as they can grow larger faster than their competitors.

This ability to anticipate external events is also seen in animals, including humans. Ever wondered why it is that you feel so much groggier when you wake up to an alarm clock than when you wake up naturally? Like plants, humans anticipate the time of morning and waking. Prior to natural waking, we see a large increase in circulating levels of the 'stress hormone' cortisol. This prepares us for the process of waking up, meaning that we wake feeling reasonably refreshed. But if we are woken up before the completion of the natural cortisol rise, as inevitably happens when an alarm clock goes off - then we are not so well prepared for waking, and feel much less alert.

In humans and other mammals, in addition to rhythms within individual cells, the whole body circadian rhythm is coordinated by an area of the brain known as the suprachiasmatic nucleus (SCN), which is part of the hypothalamus. The SCN receives input from specialised cells in the eye which detect bright, blue-rich light that's abundant during the day. This is used to set the circadian clock throughout the rest of the body using hormonal and neuronal signals sent to the rest of the tissues.

But the use of a circadian rhythm anticipate events does not merely extend to the sleep-wake cycle; they dictate the timing of a whole host of essential biological processes, from cell division and neuronal excitability to hormone release and appetite.

So what happens if the circadian rhythm is disrupted?

In recent years, advances in genetic techniques have allowed scientists to investigate the roles that various genes play in circadian timing. For example, the knockout of certain genes in mice and plants can change the period of the rhythm from its natural 24 hours to periods as short as 20 hours or as long as 28, whilst knockout or mutation of other core circadian genes can result in abolition of the rhythm all together.

A large number of human disorders are also associated with a disrupted circadian rhythm (Reddy & O'Neill 2010). For example, familial advanced sleep phase syndrome, in which sufferers experience unusually early sleep and wake times, is associated with a mutation in the circadian gene Period 2 (Jones et al. 1999). Conversely, sufferers of delayed sleep phase disorder have unusually late sleep and wake times,and this disorder has been proposed to be associated with Period 3 mutations.

Disruption of circadian oscillations is also implicated as a factor in the pathology of other diseases, particularly neurological conditions such as Huntington's and Alzheimer's diseases (Morton et al. 2004). Patients with these conditions often have disrupted patterns of day and night activity, with reduced daytime and increased night time activity, which explains why these patients are often prone to night time wandering. The tiredness which can result from this disruption is thought to add to the symptoms of these diseases.

Circadian rhythm disruption can also cause problems in non-disease states. Multiple studies have shown that people who regularly work night-shifts have an increased chance of suffering from a whole number of diseases, including some types of cancer and obesity. It is though that this is as a direct result of the lack of settled rhythm that will necessarily occur in people who consistently shift their sleep-wake cycle (Knutsson 2003).

Can we use this knowledge to help cure certain diseases?

There is certainly a great deal of potential for using our knowledge of circadian rhythms to inform and aid medical treatment. The application of this knowledge to medical regimes is often referred to as 'chronotherapeutics'.

Thus far, the application of chronotherapeutic regimes has been relatively slow in many areas of medicine. This is due, at least in part, to the complexity of drawing up such a regime. Such a large number of activities in cells and whole organisms - including the metabolism, uptake and removal of drugs - are regulated in a circadian manner that devising a regime which optimises all of these is a significant challenge.

In addition, different people can and do exist in very different phases in the circadian cycle; whilst one person may be at the classical 9am in the circadian cycle at real-time 9am, another might be at 7am or 11am. Therefore, the phase of the chronotherapeutic regime may also have to be shifted to match each patient's circadian cycle. At the current moment in time, there are few clear, definite ways of quickly ascertaining the phase of someone's circadian cycle, which again makes it difficult to optimise a chronotherapeutic regime.

That said, many of the trials of chronotherapeutic regimes which have been carried out so far have been very encouraging.Trials looking at dosage times of steroids for asthmatic patients have shown that a single 800 microgram dose of the steroid Triamcinolone acid at 5.30pm had comparable effects to four does of 200 micrograms spread throughout the day (Pincus et al. 1997). This is not seen when the single dose is taken at 8am. Although the effects of the drug are not significantly better when taken as a single or multiple doses, the ease of only taking one dose at 5.30pm might make it more likely that patients will accurately follow the treatment regime, giving better results overall.

As mentioned above, some neurodegenerative disorders are associated with disrupted circadian rhythms and sleep/wake cycles. Studies using the R6/2 mouse - a model of human Huntington's disease - have shown that using drugs to enforce a constant sleep/wake cycle in these animals can slow the progression of Huntington's symptoms seen on these animals (Pallier & Morton 2009). The hope would be that this type of regime might be applicable in human cases of Huntington's disease too.

Chemotherapy for cancer is another area where application of circadian knowledge to the dosing regime might be highly beneficial. Studies on chemotherapeutic drug administration, comparing a circadian-led application regime with more traditional steady-state infusion often used in cancer patients, have shown up to a five-fold reduction in the toxicity of the treatment (Lévi et al. 1997). As toxicity is one of the major problems with traditional chemotherapy, this is of real interest.

Many people may also be aware that it is advised that most statins (a cholesterol-lowering group of drugs) are taken just before bed. What is perhaps less well known is that the reason for this is that the synthesis of cholesterol is circadian in nature, with the vast majority of cholesterol being made at night. So, taking a drug which blocks the synthesis of cholesterol at the time when most of the cholesterol is made allows for the greatest reduction in cholesterol level.

These are just a few of the better-known examples of where the application of chronotherapy has a significant effect on clinical outcome when compared to traditional steady-state regimes. What is most striking that, when properly devised, the financial cost of a chronotherapeutic regime is not much (if at all) greater than the cost of current methods, and delivers benefits far greater than this financial increase.

This makes chronotherapeutics an attractive avenue for future investigation; it allows for optimisation of many existing therapeutic regimes with all of the benefits that this affords. And, although suggestions that, in the future, medical treatment might be administered with respect to 'chronotype' might be a little optimistic as yet, it is certainly the case that chonotherapeutics certainly should have a growing place in how we treat a wide range of conditions and diseases.