TUMOUR NECROSIS FACTOR ALPHA sounds a pretty intimidating molecule. And, indeed, it is. One of its jobs is to kill cancer cells—or, rather, to persuade them to commit suicide. But its name is a bit misleading. For TNF-α, as it is known in the trade, does more than just shrink tumours. It is one of a group of proteins called cytokines that are used by the immune system to boss other body cells around. They do so by feeding the cells in question signals that cause them to switch particular genes on or off in response to infection.

Over the past few years, there have been hints that one of these responses is fatigue. Moreover, TNF-α has been implicated in fatigue that is not associated with infection. To look into this idea further, Thomas Birchler of Zurich University Hospital and his colleagues decided to study the effect of TNF-α on the biochemical clock that keeps bodies running in sync with the sun. Their results, just published in the Proceedings of the National Academy of Sciences, show that this effect is profound and may help to explain the phenomenon of chronic fatigue.

The genes that control the body clock are most active in parts of the brain called the suprachiasmatic nuclei. However, they are—like all other genes—found in almost all cells and are frequently studied in specially cultured fibroblast cells that are easy to work with. It was on these that Dr Birchler began his investigation.

Adding TNF-α to the fibroblast system did indeed throw a spanner in the works. Six of the clock genes were suppressed by the cytokine in ways that would, in an actual animal, be expected to promote sleep. So, having proved the point in a Petri dish, Dr Birchler and his colleagues went on to see whether that expectation would be realised. It was. The same biochemical changes took place in the brains of mice, and the mice in question were far less active than untreated mice.

As a response to infection, such inactivity makes sense. Just as fever (which is also controlled by cytokines) creates an environment hostile to the reproduction of bacteria and viruses, so lethargy conserves energy that can be directed to building up the immune system—an extremely demanding task. In both cases what look at first sight to be damaging symptoms caused by an infection are actually adaptive (though unpleasant) responses to it. However, even well-evolved systems can go wrong and, just as the immune system occasionally attacks the body it is supposed to be defending, causing a so-called autoimmune disease, so it looks as though the TNF-α fatigue response may sometimes appear at the wrong time.

One example of an autoimmune disease is rheumatoid arthritis. This is often associated with fatigue, and an experiment carried out last year by Louise Pollard of King's College, London, suggested TNF-α might be involved. Dr Pollard injected fatigue-ridden arthritis patients with a protein that binds specifically to TNF-α, and thus reduces its concentration in the body. Those who underwent this treatment felt less fatigued as a result.

It is also possible that TNF-α is the explanation for the scourge called chronic-fatigue syndrome. No one knows what this actually is, nor how it is triggered. Some researchers, though, think viral infection is involved. That would certainly activate the immune system, encouraging TNF-α production—and enhanced levels of TNF-α have, indeed, been reported in people with chronic fatigue syndrome. This has generally been thought of as a symptom—and as support for the infection theory of the syndrome. But perhaps it is the cause. If so, reducing the cytokine's level in sufferers might bring them some relief.