Out of this World: The Next Generation of Medical Diagnosis

January 18, 2013

The University of Leicester (Leicester, UK) has achieved a world first by establishing a Star Trek-style "sick bay" in a busy hospital accident and emergency ward. Part of the demonstration unit uses spectroscopy techniques used for real-time air fingerprinting (RAFT) to perform rapid and non-invasive diagnosis of illness. Spectroscopy interviewed Paul Monks, Professor in Atmospheric Chemistry and Earth Observation Science - one of the key forces behind the project - to find out more.

The University of Leicester (Leicester, UK) has achieved a world first by establishing a Star Trek-style “sick bay” in a busy hospital accident and emergency ward. Part of the demonstration unit uses spectroscopy techniques used for real-time air fingerprinting (RAFT) to perform rapid and non-invasive diagnosis of illness. Spectroscopy interviewed Paul Monks, Professor in Atmospheric Chemistry and Earth Observation Science — one of the key forces behind the project — to find out more.

How did you enter the field of analyzing volatile organic compounds (VOCs) in breath?

Bizarrely, for someone who studies VOCs in breath, the answer is atmospheric chemistry. My main research interests are air quality and climate. I had a number of questions based around the rapid detection of wide ranges of VOCs in the atmosphere, and so my collaborator and I built an instrument to measure them. Having done this, we realized there were many other applications for the instrument, from food to forensics and medical.

What are the key features of the RAFT project?

RAFT is making a difference to big and small companies. The RAFT business tenet was regional-based technology innovation from the higher education sector that could be used to develop business opportunities for regional businesses based on the fast analysis of complex mixtures of gases. RAFT has been sniffing out success for a range of companies in the waste recycling, food, healthcare, and construction businesses sectors. We have worked with small and medium enterprises (SMEs) to gather preliminary data so they can leverage investment. We have developed new processes for instant detection of the ripeness of high-value fruit products. We have helped companies look at waste mitigation options for by-products of their commercial waste. From the demonstrator facility we have had a base to engage not only SMEs but larger companies who have commercial interest in the technology and expertise available in RAFT.

What do you look for in breath samples when looking for disease-related changes in the metabolome?

Breath is a mixture of nitrogen, oxygen, carbon dioxide, water vapor, inert gases, and a small fraction of trace VOCs in the parts-per-million (by volume) to parts-per-trillion range. Despite these low concentrations, trace species reflect many processes occurring in the body. Endogenous (internally produced) VOCs can be produced anywhere in the body as the products of normal metabolism. Those compounds whose concentration and nature have been altered because of disease are transported via the bloodstream to the lungs where they are exhaled in breath. The exhaled profile will represent VOCs originating from the blood; VOCs contributed from the airways, nose, or mouth; and VOCs from exogenous sources, such as inspired air.

The analysis of trace gases in breath could offer a new metabolomic approach toward disease detection. There are medical, scientific, and technical challenges in breath analysis: The biochemical generation, origin, and distribution of the VOC biomarkers need to be understood, the exhalation kinetics and sampling remain critical, and there are significant technical challenges in the move from discovery technology to bedside tests in a clinical environment. With the development of real-time analysis of breath and the ability to measure multiple components simultaneously, we are now in some senses able to fingerprint breath using a multiple marker approach. The move from the “silver bullet” single-marker approach to the interpretation of the VOC fingerprints could provide unheralded insights into human well-being and a new era from breath analysis with real time VOC measurement technology forging the way forward.

What are the challenges associated with “fingerprinting” breath?

Breath is a challenging analyte in that it is transitory, moist, and contains trace levels (parts per billion to trillion) of the target VOCs. A lot of work has gone into the breath sampling side to get reproducible sampling that can be used across a range of patients. At the moment, our main challenge is recruiting enough patients to take part in our trials.

How was selectivity introduced into RAFT? Why do you use chemical ionization reaction–mass spectrometry (CIR-MS) over proton transfer reaction–time-of-flight mass spectrometry (PTR-TOF-MS)?

We realized one way to introduce a measure of selectivity in our direct MS was to use different fingerprinting solutions (reagent ions). The radioactive source we use is quite flexible in that it will easily and cleanly ionize other reagents such as NO, O2, NH3, and methane. The reagents can either act as charge-transfer or proton-transfer reagents. With Japanese colleagues we have also been able to tune the reagent using a method of turning one reagent ion into another. All these methods use TOF-MS, which gives us all the ions all the time.

PTR-TOF-MS is a good workhorse system, but we tend to use CIR-MS when we need to look at different things. For example, using CIR-MS we have shown that you can separate nominally isobaric molecules because they have different fragmentation patterns with different reagent ions.

A major success of the project has been the integration of RAFT into a specialized sickbay at the Leicester Royal Infirmary Accident and Emergency Unit. What is the role of RAFT within this unit?

The sick-bay project was highly multidisciplinary resulting from a fusion of ideas that led to the repurposing of futuristic technologies to address real-time problems. The £1 million-plus facility brings significant clinical benefits allowing diagnosis without the use of invasive probes, blood tests, or other time-consuming and uncomfortable procedures.

Scientists use three different types of cutting-edge technology — developed and used at the University of Leicester — to detect the “sight, smell, and feel” of diseases: One group of novel instruments (developed for air pollution from RAFT) analyzes gases present in a patient’s breath; a second uses imaging systems and technologies — developed to explore the universe — to hunt for signs of disease via imaging the surface of the human body; and a third uses a suite of computers linked medical monitors to look inside the body and measure blood-flow and oxygenation in real time. The technologies employed have never previously all been used in this way and with such a large potential pool of patients.

University of Leicester researchers from space research, emergency medicine and Chemistry worked with colleagues in Cardiovascular Sciences, Infection, Immunity and Inflammation, Physics and Astronomy, Engineering, IT Services and the Leicester Royal Infirmary to create the Diagnostics Development Unit.

The technology could ultimately help develop devices akin to tricorders from Star Trek — used by medics in the sci-fi series — to diagnose illness simply by waving it near a patient.

What future developments do you predict for RAFT?

We have recently added “go-faster” stripes to our instruments through the codevelopment of a radio frequency ion funnel for one of our instruments, which increases real-time sensitivity by keeping the ions away from the wall of our reactor. We are also developing new smaller instruments, as well as hand-held devices for medical applications. The joy of RAFT is the combination of new analytical problems and cutting-edge technology.

Paul Monks received his B.S. degree from the University of Warwick and his PhD from the University of Oxford in 1991. In 1992 he took up NAS/NRC fellowship in Astrochemistry at NASA/Goddard before returning in 1994 to the UK to work a postdoctoral position at the School of Environmental Sciences at UEA. In 1996 he was first appointed to a lectureship in Earth Observation Science in the Department of Chemistry at the University of Leicester, and has now been promoted to a Professorship of Atmospheric Chemistry in 2007. He is a fellow of the Royal Meteorological Society and the Royal Society of Chemistry, the current cochair of the IGBP-International Global Atmospheric Chemistry program. and chair of the DEFRA Air Quality expert group. He is also a member of the UK Space Agency, Space Leadership Council, and Natural Environment Research Council lead body (council).

Contact Details:

E-mail:P.S.Monks@le.ac.uk

Website: www2.le.ac.uk/departments/chemistry/facilities/raft