Stars in their ions

An instrument used in astrophysics could revolutionise the diagnosis of a range of diseases
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The Independent Online

At first glance the rarefied science of astrophysics would seem to have little to offer the much more down-to-earth business of hospital medicine. But researchers at the Centre for Science and Technology in Medicine at Keele University might beg to differ. Working with doctors at the North Staffordshire Hospital, the scientists are developing the world's most remarkable breathalyser, able to detect vanishingly small quantities of volatile chemicals on human breath. The hope is that it could be used to diagnose a whole range of diseases, from kidney failure and diabetes to cancer, and even stress.

It would be remarkable enough on its own, but the underlying technology was originally devised nearly 30 years ago to help explain how molecular reactions might take place in the vast spaces between stars.

The instrument is called a selected ion flow tube (Sift). Its co-inventor is Professor David Smith. "In the early 1970s, radioastronomers were picking up a lot of signals from the interstellar clouds showing molecules whose presence was difficult to explain," says Professor Smith. To obtain fundamental information about the sort of chemical reaction there might be, he and his colleagues developed the Sift technique. This allows ions ­ charged molecules ­ to react with neutral molecules in very low concentrations and in a highly controlled way.

The Sift apparatus consists of a long tube through which helium gas is pumped. Ions are introduced at the inlet of the tube and neutral molecules ­ which it was thought could be reacting in the regions of space they were watching ­ injected downstream. The ions react with the sample molecules to create an electrically charged product, whose exact chemical identity is then determined by a mass spectrometer positioned at the far end of the tube. If the products found by this instrument matched those observed in space, they had their reaction.

"Astronomers were observing these molecules, and we were able to use Sift to say it was the ion chemistry leading to the production of the molecules," says Professor Smith.

But then the next step in Sift's development occurred to the inventors: "We realised that as well as introducing samples of known molecules to observe their reactions with the ions, we could use the method to detect trace amounts of unknown gases, and one obvious application was in the analysis of breath."

The body's complex chemistry means that if someone's metabolism is out of kilter for any reason, including disease, it will produce altered levels of the by-products called metabolites. If these molecules are small enough, they can pass through the blood-air barrier in the capillaries and alveoli in the lungs, and be carried out in the breath.

Professor Smith and his colleague Dr Patrik Spanel have developed an exquisitely sensitive breathalyser for medical use based on Sift called Sift-MS, now in use at the North Staffordshire Hospital.

Like the astrophysics Sift, the key to the medical version of the technique is to introduce different ions. But in this case, the ions are chosen because they do not react with the major components of air.

"The patient exhales through a mouthpiece into the flow of helium," says Professor Smith. "The breath enters the stream and the organic molecules present in it react with the ions. You then look at what you get in the mass spectrometer downstream. You can then work out what the neutral molecule was and its concentration. The system is fast ­ you can make many measurements in a single breath exhalation of, say, five seconds. By injecting different ions into the system you can increase the sensitivity and detect different molecules instantly.

"The beauty of it is that it is hugely sensitive, it can deliver results in real time and we don't have to use a needle to take a blood sample."

The research team has lightened the original Sift apparatus from an unwieldy 2 tonnes to around 200kg, making it transportable.

Dr Simon Davies, a consultant nephrologist at the North Staffordshire Hospital and Reader in Nephrology at Keele University, is working closely with Smith's team. "I thought this technique might be interesting in the study of renal failure, where patients accumulate abnormal molecules in the blood stream because they can't excrete them," says Dr Davies. "The initial finding with patients with kidney failure was that they had raised levels of ammonia on their breath."

By monitoring patients' breath as they underwent dialysis treatment, the ammonia levels diminished as the dialysis progressed. "It might be a way to measure the efficiency of the dialysis," says Professor Smith.

One puzzling observation concerned a molecule called isoprene. "Isoprene is a hydrocarbon present on everyone's breath, but in vanishingly small concentrations," says Dr Davies. "The Sift-MS analysis showed that our patients not only tended to have higher than normal isoprene levels but that when they went on the dialysis the isoprene increases rather than being removed. This was totally unexpected."

The reason for this increase remains unclear. An intriguing possibility is that it is a result of stress. "There have been one or two other studies where people who have had heart attacks have been shown to have elevated isoprene levels in their blood," says Dr Davies. "It could be a marker of stress."

Another important application of the method is in calculating how much water there is in a person's body. Accumulation of excessive quantities of water is a problem for dialysis patients, and often the clinical signs appear at a stage when the body is already dangerously overloaded. Using Sift-MS, it is possible to give a person a small quantity of water labelled with deuterium ­ the isotope also known as "heavy hydrogen", which contains a neutron ­ and follow the concentration of the deuterium in the breath. "After a few hours you can take a single breath measurement to work out how much the deuterium has been diluted and from that how much water is in the body," says Professor Smith.

The researchers are also working with cultured human cells in the laboratory to obtain information about the metabolic status of the cells. This could be useful for testing new drugs in the laboratory, for example.

"There has been no real, systematic research into the volatile chemicals released by cells," says Professor Alicia El Haj, head of the Centre for Science and Technology in Medicine at Keele. "This technique is allowing us continuously and non-invasively to monitor these substances, which are present only at trace levels. If we could pick up certain molecules and identify them as markers of, say, cancerous cells this would be a major advance."

The research team has also been working with Professor James Elder, Consultant Surgeon and Head of the Department of Surgery at the North Staffordshire Hospital, looking at cancers. They have detected elevated formaldehyde levels in the air space above urine samples of people with bladder cancer and prostate cancer.

The researchers believe that Sift-MS has the potential to play an important role in clinical medicine. "I think Sift-MS is something which is going to completely revolutionise breath analysis. It is a huge step forward," says Dr Davies.