Touching Lives - March 2005
Out of 600,000 live births in the UK every year, about 8,000 will be very premature and weigh under 1500 grams (about 31⁄2 pounds). Sadly around 1,600 will die, 600 will develop cerebral palsy, and many others will have a variety of disabilities. So many lives, and the quality of many more lives, are at stake.
One of the triggers of premature labour is inflammation of the membrane which surrounds the baby and holds in the protective waters which “break” at birth when the membrane ruptures. Two related research projects funded by Action Medical Research are looking at what causes the inflammation and how the body reacts to it, thus coming at the problem from different angles.
Bacteria — the external threat
Dr Mark Sullivan and colleagues are undertaking a two-year study of bacteria which may trigger an inflammatory reaction. This follows on from a previous Action Medical Research-funded project, in which modern molecular biology techniques were used to visualise bacteria in the foetal membranes and to identify any bacteria found there.
“The received wisdom is that the baby should be growing in a sterile environment,” Dr Sullivan told Touching Lives. “In practice we found many bacteria present in the foetal membranes that surround the infant, but no simple equation between bacteria, inflammatory responses and preterm labour. ^It seems that bacteria are quite commonly found within the womb; sometimes they are harmful and sometimes not.^ It is not clear why or how this happens.
“A partial gene (DNA) sequence was obtained from bacteria detected in foetal membranes and computer analysis compared this sequence with known bacterial gene sequences. This suggested that one of the possible culprits is the bacterium Fusobacterium nucleatum (F. nucleatum). The exact effects of this organism are not known, but it seems that F. nucleatum may be a particularly potent harmful bacterium.”
The first part of the current project (run by Dr Sullivan and Professor David Edwards) is to study the effects of F. nucleatum on foetal membranes in the laboratory. The tissues are donated with the full consent of parents following birth, and allow the researchers to create a ‘model’ of what may happen in pregnancy and preterm labour. They can then compare the interaction of bacteria and membranes with findings from normal and abnormal birth.
Another part of the project, run by their colleagues Dr P R Langford and Professor J S Kroll, is covering the possibility of unforeseen effects. They will study the proteins involved in the body’s reaction to F. nucleatum infection, to see which proteins have changed and how.
“In this way we avoid limiting ourselves to what we expect to happen,” said Dr Sullivan. “We can pick up on the unexpected.”
There are practical implications if the research is successful. If the team can prove that this bacterium is a common cause of pre-term labour, then doctors can start to consider the use of treatments specifically to prevent the growth of F. nucleatum, to the benefit of hundreds of mothers and babies each year.
Dr Sullivan and his colleagues at Imperial College London have been awarded over £124,000 for their Touching Tiny Lives research.
Toll-like receptors — the body’s response
Professor Phil Bennett is looking at how the body’s immune system reacts to bacterial attack. The immune system is immensely sophisticated, developing specific antibodies to fight specific infections. If you get a cold, your body produces antibodies against that particular strain of the virus. Because cold viruses mutate at such speed, the next time you get a cold you get a different strain, and the body has to start all over again to produce another kind of antibody.
However, the body has another kind of weapon in the fight against disease. It is much more primitive, and similar systems exist in other species and in plants. Called the innate immune system, it recognises a wide range of common “attacks” on the body and responds by causing inflammation. Inflammation is a positive part of the body’s protection. It is a way of summoning cells from other parts of the body to come to the rescue and attack the cause of infection. Professor Bennett describes this bit of the immune system as “wide but not deep”.
One of the effects of inflammation in the foetal membrane is to cause pre-term labour.
“In evolutionary terms, it may be good to end a pregnancy where infection is present,” Professor Bennett explained. “It may save the mother. But of course, it also endangers the baby.”
^The mechanism which is at work involves Toll-like receptors. These are proteins on the outside of the cell, whose job is to recognise the presence of viruses and bacteria.^ What Professor Bennett thinks is happening is that in some cases there is an over-reaction of these receptors to trivial infections, with devastating results.
There are 11 varieties of receptor in human beings, but little is known about which ones are involved in the process of triggering inflammation. Professor Bennett will be using the techniques of immuno-histochemistry, which involve “tagging” antibodies in the membrane, so that they glow under the microscope. From this he hopes to identify the receptors at work in individual cases.
“The problem is that not every mother responds to the presence of bacteria in the same way. We want to find out why this process is activated by some bodies and not by others. It’s a very complex interaction of linked proteins.”
If Professor Bennett identifies the receptors and the way that proteins react, it may then be possible to predict who will be at risk from inflammation triggering pre-term labour. These mothers can then be targeted for treatment either with anti-inflammatory drugs or antibiotics, as a preventive measure.
Professor Bennett has received more than £122,000 for his three-year study, taking place at Imperial College, London.We thank Mothercare Plc for their help in funding this research.
Both these projects investigating preterm labour offer the prospect of hugely important benefits to mothers and babies. Touching Lives will of course keep you posted on their progress.