First we wake it up, then we wipe it out

July 18, 2003

Tuberculosis lies dormant in about one-third of the human race. Now scientists want to end its slumber, writes Angharad Davies.

For two years, my friend's father, Ken, had to strip naked and lie under a bright light for an hour a day - 30 minutes back, 30 minutes front. Worse, as a young woman my great aunt suffered the humiliation of spending months on what was then known as the "venereal diseases" ward. She was told she must have been a bad girl and that as punishment she wouldn't be able to have babies. In fact she, like Ken, had tuberculosis - pelvic in her case - in the days before the disease could be treated.

TB was once so feared that John Bunyan called it "the Captain of these men of death". Then, in the 1940s, drug treatments became available, and eventually, many believed, the disease would be eradicated.

Yet today, one-third of the world's population remains infected with the bacterium that causes TB - Mycobacterium tuberculosis. Nature has made a concession - not all those carrying the disease will actually become ill.

Instead, the bacteria lie dormant in the body, evading the immune system, as if biding their time and stealthily waiting for the opportunity to attack.

In nine out of ten people, this never happens. In some cases, however, the weakening of a person's immunity can cause the bacteria to reactivate - for instance, during chemotherapy, HIV infection or old age. How this sudden reawakening works and what controls it are not yet known.

Why not identify all the people who are carrying the TB bacterium in their bodies and treat them with anti-tuberculosis drugs before they become ill? Unfortunately, this is not as easy as it sounds. The dormant bacteria are much less responsive to drugs than their wakeful counterparts. The chemical processes that go on inside all living organisms have been slowed right down - or even, some believe, stopped altogether. This means that the drugs, which act by interfering with these chemical processes, are unable to do their job. It's rather like trying to sabotage a car by putting sugar in the petrol tank - if the engine isn't running, nothing actually happens.

Similarly, the ability of these bacteria to become dormant accounts for the lengthy therapy needed for those who do become ill with TB. Even today, treatment takes a minimum of six months - a tall order for a well-funded and developed health system, let alone for those in poorer parts of the world where TB is rife. It is one of the World Health Organisation's stated aims to find ways of decreasing the length of treatment. To do this, a better understanding of the dormancy phenomenon is badly needed.

Recently, scientists at the University of Wales, Aberystwyth, made a breakthrough in this field. A team led by Doug Kell and Mike Young discovered small protein molecules produced by TB bacteria that appear to switch the dormant bacteria back on. It raised the possibility that this might be a means of communication between the bacteria - if one of them senses that conditions are right to come out of the dormant state, it produces these proteins as a "wake-up call" to alert the others.

The possibility of communication between bacteria is supported by evidence from the oceans. Some aquatic bacteria can produce the protein luciferase, making them glow blue-green. This benefits their host, the squid, at night.

In return for this illuminating activity, the squid allows the bacteria to live in a special light-producing organ. Since glowing is such an energy-consuming form of rent, the bacteria produce luciferase only when they detect that there are enough of them around to make the effect worth while. This is known as "quorum sensing".

So, whereas in the past scientists considered each bacterium to be a separate individual, existing independently of all others, it is now known that they produce signals to communicate with and influence one another. An analogy could be made with a colony of ants: each ant is a separate, self-contained organism that also behaves almost like a cell in the larger entity of the colony.

The TB "wake-up" proteins were dubbed "Resuscitation promoting factors".

The aim of my research is to further investigate these proteins and whether they can be used to "wake up" dormant TB bacteria in the laboratory and hence render the bacteria more susceptible to the action of anti-tuberculosis drugs. At first sight, resurrecting this particular Lazarus may seem the last thing that needs to be done. But it may be that to hit the bacteria hard with drugs, we need to switch them on first. The result could be shorter treatments and the curing of dormant disease. Ken says he's all for it.

Angharad Davies is a Medical Research Council clinical research training fellow in the department of medical microbiology at the Royal Free Hospital, London. Her essay won the 2003 MRC's Max Perutz essay prize, which was presented last week.

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