The art of noise

As any parent knows, ultrasound has been used for years to check on the health of unborn babies. But now scientists have discovered that it can kill cancerous tumours too
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For most of us, the word "ultrasound" probably conjures up a grainy scene of grey and white swirls which, with guidance from a skilled radiographer, we can more or less accept as being an image of a baby developing in the womb. For decades ultrasound has been used as an important technique for imaging within the body, particularly to check the health of the growing foetus in pregnant women. It is safe, cheap and reliable. But now ultrasound is beginning to find new roles in medicine, from "acoustic surgery" - killing cancerous tumours without recourse to a scalpel - to potentially helping to deliver drugs, and even genes, into cells.

Ultrasound is sound that is beyond the range of human hearing - generally defined in physics as sound with a frequency of more than 20,000 hertz. It is propagated as a wave, and travels by the mechanical vibration of molecules through a medium. Ultrasound waves are generated by devices called transducers, which contain "piezoelectric" materials. These vibrate at given frequencies when an electric field is applied to them.

"For many years ultrasound has been used in diagnostic medicine by using a pulse-echo technique," says Professor Tim Mason, the director of the Sonochemistry Centre at Coventry University. "A pulse of high-frequency ultrasound is sent out and the returning echo is detected. By calculating the time difference between the pulse and echo it is possible to construct an image of what the wave has encountered."

For medical imaging the ultrasound has low power. It can penetrate the skin but does not have sufficient energy to do damage. But for decades medical scientists have pondered how to harness ultrasound energy to destroy unhealthy tissue within the body - cancerous tumours, for example.

Simply to increase the energy of the sound wave, by lowering its frequency, would not work. As soon as the sound wave encountered the surface of the skin it would heat it up dangerously. "But if you took two high-frequency beams - each on their own being harmless - and directed them into the body from two different points, where they intersect you would get twice the energy," says Professor Mason. "So if you had several beams meeting at a point, you could obtain sufficient energies at the focus to heat up tissue and kill it at that specific point." This is called high-intensity focused ultrasound (Hifu).

Professor Gail ter Haar is head of ultrasound therapy at the Institute of Cancer Research at the Royal Marsden Hospital in London. "We have been researching Hifu for more than 20 years and built the first clinical prototype, which has been tested on 74 patients with various types of cancer," she says.

"Everyone recalls as a child using a magnifying glass to focus the sun's rays to a point where you can burn a hole in leaves or paper. It is only at the focus that the rays are powerful enough to cause burning. Hifu works in the same way. We take a source of ultrasound outside the body and focus it on the target tissue."

The ultrasound beam is generated in a concave-shaped transducer, so that the waves emanating from the transducer converge at a point some distance from the source. At the focal point, a few millimetres across, tissue is heated to around 56C or higher, sufficient to kill the cells at that point without damaging the neighbours.

"One of the main difficulties has been in monitoring what is happening," says Professor ter Haar. It has been necessary to alternate Hifu treatment with ultrasound imaging to monitor the therapy, making the process time consuming. Nevertheless, says Professor ter Haar, "where we have targeted tumours, it has been very successful in killing tissue."

Another approach being investigated by the team is in sealing off the blood vessels that feed tumours. A short burst of Hifu can cauterise small blood vessels, and it is possible that this could be a way of "starving" cancers of their blood supply. Researchers at the Royal Marsden are hoping to obtain funding to build a second system.

Meanwhile, a new Chinese system has been developed that could bring the technique closer to routine use. The machine, the first Hifu instrument of its type and the only one in the West, is being tested on patients at the Churchill Hospital in Oxford.

Tim Mason was instrumental in bringing the Chinese device to the country. "I was in China in 1999 examining a PhD student when I was invited to a hospital in Chongqing to see this machine," he recalls. "I was very impressed with it, and at the time was talking to investors who were interested in developing a Hifu system. The Chinese system was very close to what they had in mind, and they agreed to invest in the technology."

A machine is in use at the Churchill Hospital and is undergoing clinical trials on patients with advanced liver cancer. The Chinese system has overcome the monitoring problem by having an imaging ultrasound transducer alongside the Hifu transducer, so that the treatment can be observed as it is being done.

"I think as a therapy Hifu is enormously exciting," says Professor ter Haar. "For liver cancer there is often little that patients can be offered, and here we have a potential for using something that does not require surgery, and as far as we know the Chinese system has been very successful."

Ultrasound is also finding other new applications in medicine. At the University of Wales College of Medicine, Dr Nazar Amso and his research team are working with colleagues at Cardiff University to investigate the effect of ultrasound waves on the porosity of cell membranes.

Many medical interventions require large, unwieldy molecules to enter cells across the cell membrane. This can often be difficult to achieve. One possible way of increasing the "leakiness" of cells is to expose them to ultrasonic waves. "We have developed unique techniques for studying what happens when cells are put in the path of ultrasound," says Dr Amso. "We have demonstrated conclusively with red blood cells that we can induce changes in the appearance of the cell's membrane that had been correlated in the past with an increase in the membrane's permeability - a phenomenon called sonoporation."

The researchers are now planning experiments with cell cultures to see if similar effects can be produced in a more complex cellular system. If ultrasound can be shown to increase the porosity of cells in the body safely and reversibly, it could have important applications in many areas.

In chemotherapy for cancer treatment, for example, it is vital that the potent toxic drugs that are administered have a minimal effect on the patient's healthy cells. By directing an ultrasonic wave on to the cancerous tissue when the drug is administered, it might be possible to ensure that the drug is taken up preferentially by the more permeable cancer cells.

Dr Amso's speciality is in reproductive medicine. Freezing human eggs or other reproductive tissue can be difficult. Upon thawing, the cells are often irreparably damaged. One way around this is to insert cryoprotectants into the cells, which prevent damage during freezing. However, these often large molecules require a special carrier molecule to get them across the cell membrane. Unfortunately, the carriers themselves are often potentially toxic. "If we could enable large cryoprotectant molecules to enter the cells without the need for the carriers, this would be a significant advance," Dr Amso says.

Another important potential application could be in gene therapy, where genetic diseases are treated by inserting healthy genes into faulty cells. For years scientists have struggled to find safe and efficient methods of inserting the genes. Sonoporation of the cells could provide a new route.