Life on earth

Medical technology can come from anywhere. That might seem obvious, but until fairly recently, relatively little technology has been transferred from engineering to medical applications. And that’s something that the Wellcome Trust, the world’s largest medical research charity, is keen to tackle. The trust is currently funding a project — set to enter clinical trials later this year — to convert a device designed to analyse comets and to search for life on Mars into a portable tool to diagnose tuberculosis in the most rugged environments of sub-Saharan Africa.

Glenn Wells, head of business development for the Trust’s technology transfer operations, said the development of medical devices was a highly multidisciplinary activity, needing the input of engineers, biologists and clinicians — three groups that are unlikely to collaborate. ‘Engineers have often not realised their research might have medical applications,’ he said. ‘And as far as the Trust goes, they didn’t know we existed, or that they could apply for grants from us.’

One scientist who was aware of Wellcome was Colin Pillinger of the Open University, the guiding force behind the (ultimately ill-fated) Beagle 2 Mars lander. Pillinger secured funding from the Trust to develop the gas-analysis package for Beagle 2. The award stipulated that, after the mission, the technology had to be translated to biomedical applications, and this task was entrusted to Pillinger’s colleague, Geraint Morgan.

The Open University already had experience of building miniaturised analysis devices, said Morgan. ‘Colin was principal investigator for the Rosetta mission, which is an ESA comet-chaser,’ he added. Rosetta was launched in 2004, and is scheduled to send a washing machine-sized lander on to the surface of a comet in November 2014. That lander will contain a mass spectrometer known as Ptolemy, designed by Morgan’s team. ‘It’s about the size of a shoebox, weighs the same as four bags of sugar and uses as much power as a lightbulb,’ he said.

Ptolemy will analyse samples of the comet’s nucleus and provide information on its composition, which could help determine whether comets were responsible for bringing water, or even the first organic compounds that eventually led to the evolution of life, to the newly formed planet Earth.

The team then adapted Ptolemy for the Beagle 2 gas analysis package, which was again intended to look for organic compounds. And this, with some refinements, is exactly what the device would do to diagnose TB.

There is a huge need for rapid and sensitive TB diagnosis in the developing world. Its incidence is climbing rapidly, and HIV with TB is now the biggest cause of death in Africa. In 2005 — the most recent year for which reliable statistics are available —the World Health Organisation estimates there were 15 million people with TB in the world, with 8.8 million new cases and 1.6 million deaths. Incidence rates are climbing fast in sub-Saharan Africa and Eastern Europe because of the rise of antibiotic-resistant strains and extreme virulence of TB — it is passed on by coughing, and it is easy to catch. Of the 22 countries with the highest incidence of TB, nine are in sub-Saharan Africa, said the WHO.

It is believed one-third of all people have latent TB — that is, the bacterium is present in their lungs, but a healthy immune system will keep it suppressed. But if the immune system is compromised, the disease will quickly overwhelm the body. The average life expectancy for someone with HIV and TB — which represents about half of all TB sufferers in Africa, and up to 80 per cent in some regions — is just 56 days.

The Wellcome Trust’s interest in the mass spectrometer stems from an urgent need for a rapid and sensitive diagnostic test for TB to use in the developing world, and it has invested £1.3m in developing the device for this application, plus £1m from the Open University.

‘When we were talking to the trust, it was clear that TB and HIV is their number one priority,’ said Morgan. ‘For most people in resource-poor societies, the main diagnostic technique is smear microscopy — an operator looks at a sputum sample under a microscope and checks to see if the bacterium is present.

‘But in seven out of 10 cases, that won’t detect TB. So if someone comes to a clinic with a cough, they’ll be given some antibiotics to kill off any other infections and asked to come back, and they have to keep coming back until there’s enough TB in their sputum to be detected. In most places in Africa, they have to come back up to 10 times, and that’s very hard for people in remote locations.’

There is a more sensitive test, which involves sending the sample away to be cultured. But TB cultures very slowly, and it takes six to eight weeks to produce a diagnosis — and by that time, for many patients it’s too late to start treatment. And it is often a logistical nightmare to send a sample to a remote reference laboratory and get the results back.

For the Wellcome Trust, the Prospero-based mass spectrometer — actually a gas chromatograph-mass spectrometer (GC-MS) combination — could be a solution. Small enough to fit into a box the size of a large briefcase, the system could be taken to patients even in remote settlements.

The operator would feed in a sputum sample, which would then be bombarded with high-energy electrons to split apart the organic components into charged fragments. These are then swept in a curved path past an array of electromagnets, which deviate the fragments from their trajectory by an angle that depends on the ratio of their mass to their charge. The magnetic field is altered to sweep all the charged fragments in the sample on to a detector at the end of the curved path, and inbuilt processors analyse the detector signal to build up a picture of all the different-sized fragments. This can be used to determine which molecules were present in the original sample.

‘The TB bacterium has a distinctive coating made from a protein,’ said Morgan. When fed into a GC-MS, this coating fragments in a characteristic way, and the system will search for these fragments. Detecting them would be a definite diagnosis of TB.

Morgan’s team has now redesigned the Ptolemy system for TB diagnosis. ‘It needs to be portable, robust, and ideally use as little power as possible,’ said Morgan. In fact, it has turned out to be a significantly less complex design than Ptolemy and the Beagle 2 gas-analysis package. For one thing, because it isn’t going into space, it hasn’t required radiation shielding. And because it isn’t operating in a vacuum, it doesn’t need to incorporate all its own gas supplies.

Also, the detection system is simpler, said Morgan. ‘This machine will only be looking for the molecular fingerprint of TB, so we can design it specifically for that.’ This affects both the hardware and the analysis software, which is being developed at Cranfield University.

Simplicity is the key to the instrument, because the people operating it are more likely to be health workers from clinics than doctors or nurses. ‘The operator and instrument interfaces are important considerations because we’re trying to make this box as simple as possible to operate in the field,’ said Morgan. His team is working with Cranfield and the project’s clinical partner, the London School of Hygiene and Tropical Medicine, to ‘de-skill’ the machine.

For Wellcome, this approach has several advantages. ‘Point-of-care diagnositics is an obvious target for us,’ said Glenn Wells. ‘Rapid detection of a pathogenic agent is key for a good treatment regime, and that can be used both in developing and developed countries, as long as they’re robust enough, and have a big benefit.’ Proving a technology in rural Africa or India is a good test of its robustness, he points out: ‘If it works out there, it’ll definitely work for a GP in the UK.’

As for the mass spectrometer, tweaking the detector and analysis software would make it suitable for diagnosing other diseases. ‘It would be a fairly minor adjustment to the system,’ said Morgan.

But for now, the team is concentrating on Africa. Over the next six months, it will convert its current experimental prototype into a packaged, pre-production model, and is working on the onboard analytical chemistry to make the detection/analysis part of the device as robust as possible. In October, the LSHTM will take this version out to Africa for intial testing.

‘At the end of the two-year project, we’ll hopefully have a box that can go out to a clinical trial, then we can go to the real world and start addressing this problem,’ said Morgan.

UPDATE:

ESA’s Rosetta probe reached its intended orbit around comet 67P/Churyumov-Gerasimenko in August 2014