What makes us tick?
John Ankers, University of Liverpool
From the changing seasons to our daily sleeping patterns or the beating of our hearts, biological cycles are all around us. What we now know is that some of these very different natural cycles work together like cogs or gears in a giant clock. Understanding how these clocks work (and how they can go wrong) might bring new hope for treating diseases such as cancer.
In the northern hemisphere, the passage of the Earth around the sun gives us cold winters and warm summers. These, together with daily tidal patterns controlled by the moon’s orbit and a day-to-night cycle driven by a constantly spinning planet, put considerable strain on life on earth. How have plants and animals adapted to deal with such dramatic changes?
Imagine a huge, but invisible, clock. Environmental changes brought about by the sun and the moon turn cogs in this clock. The seasonal cog moves around once per year, the day-to-night cog is smaller and turns every 24 hours. These cogs are linked: as the earth moves around the sun, not only do the seasons change but the days get longer or shorter. Plants and animals have their own invisible clockwork. Each turn of the Earth’s light/dark cycle creates “circadian” (Latin meaning “about a day”) patterns of daily growth in plants and sleep in humans. The mechanics of the circadian cycle are complex, having evolved over millions of years, and sensitive to unexpected changes in the environment. This allows, for example, humans to react to abnormal periods of light or darkness (which may be experienced as jet lag) or plants to change their metabolism to compensate for a particularly harsh winter.
Many of the cells in the human body are repaired or replaced continuously (skin cells replace roughly every day, whereas nerve cells are never replicated). Fortunately for our clocks, this “cell cycle” is governed by a number of failsafes, ensuring that the correct cells are replicated in the correct way, and that this doesn’t happen too slowly – leading to problems in early development, or too quickly – leading to the possibility of tumour formation. There has been much work done (and a Nobel prize awarded) on the discovery of proteins that regulate the pace of cell division. The cell cycle is mechanically connected to our daily circadian cycle (their cogs are linked), suggesting that the human body might be able to renew itself more efficiently at different times of the day or night. Recently, the cell cycle has been shown to interact with an intriguing group of different cogs. These much smaller, faster cogs (cycling from 100 minutes up to 6 hours) can be “hooked up” to the clockwork when they receive emergency signals – such as the need to respond to an infection, or if DNA inside the cell is damaged – freezing the cell cycle of a faulty cell before it can be replicated so that threats may be averted or any damage repaired.
All of this makes our clock incredibly complex. Nevertheless, many of these cogs are turning now, in every cell in your body. Some are accelerating, stopping and restarting whilst some are checking, repairing, destroying and rebuilding, and it is the links between these cogs that have dramatic effects on the overall clockwork, and hence the health of our cells and tissues. So what happens to the clock in diseases like Alzheimer’s or cancer? And how do we, as observers, even contemplate fixing a faulty clock?
One of the reasons cancer is so difficult to treat is that a faulty cog in our clock (such as a cell cycle that is cycling too quickly) may be joined to many other “healthy” cogs such as those driving DNA replication and repair or the response to infection. Chemotherapeutic agents are used to destroy cells in the body with faulty cell cycles, but by doing so may also interfere with some other healthy cogs leading to severe side effects. Think of the challenge in repairing one faulty cog in the workings of a grandfather clock without disturbing the rest. Now imagine doing that whilst all the cogs are moving!
But it isn’t all bad news. Such a complex problem is being tackled in new and fairly unorthodox ways. My field, that of “Systems Biology”, is devoted to reconstructing the mechanisms that beat, pulse and oscillate inside the human body as computer models, just as an engineer might build a computer model of a plane or a skyscraper to identify and correct problems in its design. These models allow us to “virtually” unpick the clockwork of the human cell to see what makes it tick, and then probe and prod various parts in a way that might be too costly in the laboratory or unfeasible during surgery.
As we begin to understand more about how the clockwork of the cell is connected – how large, slow cogs wheels such as changing seasons, the circadian clock or cell cycle turn with smaller cogs like those driving emergency responses (or even smaller cogs cycling every few seconds like those driving electrical pulses in the heart or nervous system) – we may be able to design combination treatments that exploit the links between them. Slowing the cell cycle temporarily, for example, might allow a second drug to prompt a response to infection, which would otherwise have been blocked. Although there is still much to learn about our internal clockwork – exactly how connected are all of these different cogs? Are there any we have yet to discover? – the ability to help a diseased cell to repair (or re-set) itself no doubt offers an exciting prospect, and is surely only a matter of time.
