The instruction on medication to "take three times a day" is so familiar that few of us would question its origins. But a scientific revolution sweeping through the pharmaceutical industry may soon consign it to medical history. It's known as systems biology, a bland name for an emerging science whose implications are anything but run of the mill. For decades, researchers have sought to unravel the mysteries of life by focusing on its most basic components: genes. Made up of long sequences of chemicals forming the famous double helix molecule DNA, genes form the instructions used by every living cell.
Yet despite the huge effort poured into this "reductionist" view of biology, the payoff in terms of new drugs for conditions like cancer and heart disease has been meagre. It's now clear that in the search for medical breakthroughs, understanding genes alone is not enough. Attention is now focusing on the host of factors that affect the behaviour of genes, from interactions with other genes to their physical location in organs. Understanding this incredibly complex web of interactions is the aim of systems biologists.
Their principal tools are not test-tubes or laboratory animals but supercomputers, whose number-crunching power allows simulations of the behaviour of entire living cells and even organs - with results likely to transform medical research. Last month, scientists gathered at the International Conference on Systems Biology in Gothenberg, Sweden, to hear the latest results emerging from such computer simulations. And among the highlights was a study by researchers in the UK into one of the most basic yet neglected factors affecting the behaviour of cells: the time of day.
From bacteria to blue whales, all life follows the same roughly 24 hour circadian cycle of activity and rest. Its driving force seems obvious: the daily rising and setting of the sun. Yet a simple experiment first performed more than 250 years ago reveals an unexpected twist. Intrigued by the way plants open and close their leaves each day, the French scientist Jean Jacques de Mairan put a heliotrope in a dark room, to see how the plant would respond to being robbed of its daily cue. To his astonishment, its leaves continued to open and close, apparently in response to the ticking of some internal clock of its own.
Following de Mairan's pioneering work, researchers found that when deprived of the cues provided by the sun, organisms settle down to so-called free-running cycles that are close to 24 hours. In the case of humans, experiments revealed the cycle to be around 24.5 hours long. Yet the location and nature of the internal "clock" responsible for this cycle remained unclear. The first big clue emerged in the late 1960s, when scientists identified a collection of nerve cells in the brain known as the suprachiasmatic nucleus (SCN). Linked to photosensitive cells in the eye, the SCN senses daylight and triggers the release of hormones like melatonin, which keep body functions in synch with the time of day. Then in 1995 researchers at Massachusetts General Hospital isolated nerve cells from the SCN, and found they could maintain a circadian rhythm without help from daylight. Finally, in 1997, scientists at Northwestern University in Illinois, found a gene that regulates the daily rhythms of cellular activity in mammals, including humans.
Such connections between genes, cells and the time of day is a classic example of systems biology - and one with major implications for drug design. For despite the medical mantra of "three times a day", doctors have long suspected some drugs work better when given at a specific time of day. In the mid-1980s, William Hrushesky of the University of South Carolina published a pioneering study of patients with advanced ovarian cancer who were given one of two standard drugs - cisplatin and adriamycin - either at 6am or 6pm, with the other being administered exactly 12 hours later. The results showed that those given cisplatin in the morning followed by adriamycin in the evening suffered a far higher rate of toxic reaction than those receiving the same drugs in reverse order. Similar findings have been discovered by other researchers. Yet despite their obvious relevance to patients, such findings have yet to be put into practice - not least because the benefits of correct timing aren't believed to be worth the added complexity they bring to treatment.
That could soon change, in the light of research presented at last month's systems biology conference. Dr David Orrell of the UK-based pharmaceutical consultancy Physiomics presented the results of simulations of how timing of medication affects how a drug interacts with cells. Dr Orrell and his colleagues have created a computer model of a living cell, complete with the kind of internal "clock" known to regulate its behaviour over the course of a day.
They have also simulated a real-life drug code-named CYC202, which is currently undergoing trials for use against lung cancer. The drug works by interfering with cell division - the process which, when uncontrolled, turns healthy cells cancerous. As so often with cancer treatment, the challenge for doctors is to target the cancer cells while doing minimal harm to healthy cells. The computer simulations revealed that if the drug is given at the wrong time of day, it affects the division of healthy cells as well as cancerous cells, producing toxic side effects. But if given 16 hours later, the healthy cells are no longer susceptible - while the cancerous cells, which are constantly dividing, still feel the full effect of the drug.
More research is needed to find ways of identifying the optimal treatment time for each patient - and to minimise the inconvenience of taking the drug. But these early insights from the emerging field of systems biology suggest that, in medicine as in so much else, timing is everything. Robert Matthews is a Visiting Reader in Science at Aston University, Birmingham, England www.robertmatthews.org
