Wednesday, 23 July 2014
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Breath Taking: next generation diagnostic technology

Diagnostic ’breathalysers’ could soon enable doctors to rapidly spot conditions ranging from lung cancer to schizophrenia.

The red-shirted crew member of the USS Enterprise gurgles and collapses. Dr Leonard McCoy, the crotchety but efficient medical officer, rushes to his side, pulling his diagnostic Tricorder from its holster, and passes the warbling device over his stricken comrade. ’My God, Jim,’ he says to his friend and captain, James T Kirk. ’He’s been infected with some sort of engineered virus that’s interrupted his brainwave patterns.’

’Fascinating,’ says science officer Spock, raising an enigmatic Vulcan eyebrow.

Spock may well have been wondering how on Earth (or any other planet) an entirely non-invasive, non-contact device could possibly come up with such a specific diagnosis in barely seconds. And since the first series of Star Trek screened in the 1960s, generations of doctors have wondered the same, looking on with envy. Will we have technology like that in the 23rd century, they wondered?

 

P24_MAGNIFIED.jpg

The Purdue breath sensor ’hotplate’ with a highly porus metal surface (shown inset)

In fact, they might have something rather like it in the 21st. Doctors and engineers are getting together to devise non-invasive diagnostic devices based on sensor technologies and spectroscopic techniques to provide quick diagnoses of a number of diseases and conditions, with UK researchers and companies in the lead.

The first incarnation of the ’Tricorder’ appears likely to be a piece of equipment similar to a breathalyser. Several groups of researchers are working on devices that use a variety of methods to identify and quantify compounds that are exhaled from the lungs and give telltale clues to different diseases.

For example, the presence of the organic compound acetone in the breath is a give-away that the patient is diabetic. A related compound, acetaldehyde, can indicate lung cancer. Other simple compounds that could be detected in the breath are hydrogen cyanide, which is associated with an infection sometimes seen in the lungs of cystic-fibrosis patients; ethane, a simple alkane, which can indicate schizophrenia; and pentane, breast cancer or rheumatoid arthritis. More complex mixtures of chemicals can be indicative of liver damage, lung disorders, different types and stages of cancer and even states of consciousness - pre-coma and coma states lead to changes in the metabolism that are associated with the production of certain characteristic compounds in the lungs.

While chemical-detecting sensors have been available for some time, the low concentration of marker compounds in breath has prevented the development of usable breathalysers.

Some of these breath clues have been used by doctors to diagnose disease for many years. Indeed, the characteristic smell of liver disease even has a Latin name: foetor hepaticus. However, the development of miniaturised yet accurate sensor technologies and the increasing speed and low cost of computerised analysis is now leading to the development of devices that can use this old knowledge in a more systematic, quantified way that does not need invasive tests, requiring the sampling of blood or the removal of tissues by biopsy.

One such project is currently under way in the US at Purdue University in Indiana. Led by materials scientist Kurt Bernstein and also involving researchers from the US National Institute of Standards, the team is looking at the problem of measuring concentrations of compounds in breath in real time.

While chemical-detecting sensors have been available for some time, the low concentration of marker compounds in breath has prevented the development of usable breathalysers, according to Purdue team member Carlos Martinez. ’People have been working in this area for about 30 years, but have not been able to detect low-enough concentrations in real time,’ he said.

The team is using a relatively simple conductance device - a film of a conductive material mounted on top of a very small heating unit. When chemicals pass over the film, they bind to its surface and change the material’s conductance.

The first stage for the project has been to make a sensor that can detect the presence of any compound bound to the surface; the team did this by coating micron-sized polymer particles with nanoparticles of metal oxide, placing a drop of a suspension of this mixture onto a 100-micron square ’micro hotplate’, printed with interlocking electrodes, drying the suspension and then heating the electrodes. The polymer burns away and leaves a porous metal oxide film that increases the sensor’s surface area, allowing it to adsorb more molecules of marker compounds and therefore increasing its sensitivity. The team claims that the sensor can detect acetone in simulated breath in the parts-per-billion range.

Other projects are using spectroscopic analysis to gather more detailed information about marker compounds.

The next stage, Martinez said, is to fine-tune the sensor so that it can distinguish between different marker compounds. However, even with this functionality, he doesn’t see the device as providing a hard-and-fast diagnosis. ’We are talking about creating an inexpensive, rapid way of collecting diagnostic information about a patient. It might say “there is a certain percentage chance that you are metabolising a specific compound indicative of this type of cancer”, then additional, more complex tests could be conducted to confirm the diagnosis.’

Other projects are using spectroscopic analysis to gather more detailed information about marker compounds. At Oxford University, a team led by Gus Hancock is developing a system based on a variant of infrared spectroscopy that the researchers claim can detect several compounds simultaneously, at levels below 10 parts per million.

Mars Rover

Space travel: the Mars Rover is using the basis of the Leicester sick-bay-bed biosensor


The team is working with Hancock’s spin-out company, Oxford Medical Diagnostics, on a technique called cavity-enhanced absorption spectroscopy (CEAS). This technique bounces light from a laser around a chamber - the cavity - to excite specific chemical bonds in the gas in the chamber. As the light bounces, it passes through the cavity several times. This enhances the sensitivity of the technique.

Hancock’s team has developed a variant of CEAS that replaces the laser with a component called a superluminescent light-emitting diode (SLED), originally developed by the telecoms industry. Unlike a laser, these produce light across a narrow range of wavelengths that can be separated and scanned across the sample. Meanwhile, lasers, with their single wavelength, can detect one particular bond in a small molecule. The wider range of wavelengths allows the device to detect several similar bonds and therefore characterise larger molecules. The team has also coupled together several SLEDs to scan a wide range of wavelengths, which allows the researchers to look for several compounds at the same time.

Test-based diagnostics, Coats argues, have led doctors away from the basics of their profession.

The company is initially targeting the detection of acetone for the diagnosis of diabetes, a condition that is still often misdiagnosed; a recent survey of GP practices in Surrey found that four per cent of people diagnosed as diabetic either weren’t, or had a different form of the condition than they had been told. This could mean that some 50,000 people in the UK are receiving treatment that they don’t need, while another 50,000 are being treated for the wrong kind of diabetes.

Another possible application is for athletes and gym users, who could use the breathalyser to determine how much fat has been burned during an exercise session.
One of the most ambitious projects, aiming at screening for a far wider range of conditions, is currently under way at Leicester University. Here, Prof Mark Sims, a biologist with an interest in space science, is working with emergency medicine specialist Prof Tim Coats to develop what they are specifically calling the Star Trek sick-bay bed.

Test-based diagnostics, Coats argues, have led doctors away from the basics of their profession: looking at the patient, feeling the pulse and learning the characteristics of disease. ’Invasive measurement and monitoring has several drawbacks,’ he said. ’It’s unpleasant for the patient; it can itself lead to complications such as infections; it can involve the use of radiation, which is hazardous; and it still carries the risk of false positives and negatives.’

The sick-bay-bed idea doesn’t just include a breathalyser to detect the telltale traces of disease-related marker compounds; it also brings engineering knowhow into the simple act of looking at the patient. Everybody knows that sometimes people just don’t look well, Coats said, but sometimes this can be systematised: anaemia makes you look pale, as does internal haemorrhage as the body shuts down the blood supply to the skin to redirect it to vital organs; liver problems lead to jaundice; a grey or waxy skin tone can be indicative of heart problems. All of these can be detected and measured by appropriately programmed machine-vision systems.

For example, added Coats, the yellow skin colour of jaundice is caused by the build-up of the pigment bilirubin. Spectral analysis of the colour of the skin could reveal the level of bilirubin and, therefore, the extent of liver damage. Similarly, kidney failure causes the build-up of urea in the skin, while the pallor of anaemia comes from a lack of haemoglobin; these could also be measured by spectroscopy.

Other sensors in the sick-bay bed could include blood-flow measurement via the surface of the skin and techniques such as thoracic electrical bio-impedance, which measures the performance of the heart by looking at changes in the way the body conducts electricity (this indicates the volume of blood circulating).

Sims is working on the molecular recognition side of the project, using the same techniques he is developing for the LifeMarker chip that will travel to Mars on the European Space Agency’s Mars Rover in 2018. These include low-cost sensors that detect the concentration of organic chemicals; on the Rover, these form the pre-conditioning unit for the LifeMarker, selecting samples that will then be subjected to further analysis. ’Looking for life on Mars is fun, but I get just as much fun looking for ways to apply this science to our world,’ said Sims.

 

radical remedy
eyes on the prize

AI physician device must diagnose a patient and recommend treatment

Tricorder

Dr McCoy’s fabled Tricorder, from the original Star Trek series

Next-generation diagnostics is among the subjects being considered by the X-Prize Foundation, the organisation devoted to encouraging radical technological

breakthroughs in what it calls ’humanity’s grand challenges’.

The Tricorder X-Prize would be aimed at the development of an ’AI physician’, which could be used reliably in a variety of situations. The device would need to diagnose a patient at a cost of less than $1 (£0.62) per reading and provide a recommended course of treatment; it would also have to be compatible with mobile ’cloud computing’, uploading and receiving data wirelessly from other computer systems.

The goal is to develop a device that is suitable for use not only by doctors but by clinical workers who might not have access to intensive training, or even by the patient. This would make it suitable for clinics in the developing world.

 

nanobots: a voyage of discovery

While new types of sensors are at the forefront of non-invasive diagnostics, an even more advanced variety may prove itself in more invasive treatments. Nanobots, trailing masses of expectation from decades of science fiction, are slowly becoming a reality, and sensor technology, miniaturised to the smallest level, will be a crucial part of their make-up.

In reality, nanobots are unlikely to be anything like the microscopic submarine of the 1960s film Fantastic Voyage. Rather, they will be highly advanced drug delivery systems - drugs packaged within a framework of engineered molecules that will enable them to move through the bloodstream, detecting the site where they will be needed (such as a tumour or a blood clot) from a chemical trail and dispatching a cargo of active ingredients at the precise spot where it can do the most good and cause the least harm.

One startling way nanobots could navigate is a biological computer based upon the molecule that dictates everything about us: DNA. Capable of encoding, manipulating and storing data, DNA has been used in rudimentary computer-like systems since the 1990s. Muang Nyan Win and Christina Smolke of Caltech have developed a method to use its related compound, RNA, to form a logic gate, the basic unit of computing hardware.

The gate works within a living cell, using three sections of RNA. One acts as a catalyst for protein reactions; another encodes a process for making a green fluorescent protein; the third is a trigger for the first and is customisable to be able to bind onto specific molecules that the researchers choose. These could be proteins, enzymes or drug-active ingredients.

Left alone, the system happily produces the green protein. When the trigger RNA recognises its target molecule, it effectively ’unleashes’ the first RNA section, which destroys the protein-encoding RNA. Production of the green protein is cut off, indicating the presence of the target compound.

In computing logic terms, this is a NOT gate: it stops doing something when a certain condition is met. Using two RNA strands as the trigger would make it a different kind of logic system called a NAND gate, whose output depends on two conditions. This is a very powerful type of system, because combinations of NAND gates can form any logical operation - the basis for a cell-borne, microscopic computer system, albeit a simple one.

Stringing together several logic systems could form the hardwired programming for a cell-based device that could cruise the bloodstream, looking for a number of conditions. Once those were satisfied, it could produce the required output - a stream of tailored molecules designed to affect the body. A designed, living nanobot.


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