Medical ➾
Nicholson is looking for “98%sensitivity on specificity.We know we can get that level of accuracy.” DrManfred Spraul, director of NMR
applications at Bruker BioSpin, which manufactured the NMRmachine in question, describes what drives this high resolution scanner. “At the heart of the NMR is a super-conductingmagnet which has a field strength of 400MHz. It has to be kept cool with liquid helium, at a temperature of 4K. This is needed because themagnet’s wires have to be super- conducting,” says Spraul. As a safetymeasure, themagnet has a
second coil outside themain one. “This reduces the residual stray fields outside the magnet so that even people with pacemakers can pass by close to the magnet,” adds Spraul. Samples of tissue are placed inside the
machine and subjected to a radio frequency (RF) pulse centred at 400MHz, to excite the proton nuclei of thematerial. “Excited nuclei release their energy in a way typical of their chemical environment. This is what we’re tracking,” says Spraul. To optimise the discrete resonances, the sample is spun at up to 4KHz once inserted into themagnet. As the frequency at which the proton
The 20 minutes has to be compared to the work of a pathologist
nuclei of each chemical component will resonate is different, the RF part of the instrument has to generate a range of frequencies. “Having an adequately broad RF excitation profile allows us to excite all protons. This way we can see themall at the same time,” says Spraul. While this is standard for NMR
machines, the level of automation in this model has led to the breakthrough in terms of providing results so quickly. “The 20 minutes has to be compared to the work of a pathologist. The fastest I‘ve ever heard is getting results in an hour, but usually this takes longer,” says Spraul. An innovative sample changing device is
the key. It can hold up to 48 samples, placed inside small ceramic rotor tubes which a robotic armcan pick up and transfer to themagnet for analysis when required, using a tube-post system. The sample changer also incorporates a
cooling device. This keeps samples at somewhere between -16°C and -20°C. “This is absolutely vital as tissue samples degrade very fast at roomtemperature,” says Spraul. Use of barcodes on each sample prevents
mix-ups while havingmore rotor tubes prefilled with samples ready for analysis allows longer, unattended operation.
30 ◆ Environmental Engineering ◆ February 2011
Health service: Professor Jeremy Nicholson and his fast-reacting tissue testing equipment The testing time of 20minutes, which
includes around fiveminutes of sample preparation and transfer into themagnet, allows for usually two tests for analysing molecules such as lipids, proteins, amino acids and sugars such as glucose. In terms of output, the Bruker BioSpin
machine, which operates with standard PCs, can even be configured to give a simple, traffic light-style read out. “It can be calibrated to automatically differentiate between cancerous, benign or healthy tissue,” adds Spraul. While his company is providing these
machines to teams of clinicians in Norway, France and Korea, among others, Spraul regards Nicholson as a world leader in metabonomics and agrees this technique
The intelligent knife
The next step in Nicholson’s quest to bring the laboratory into the operating theatre involvesmass spectrometry. The plan is to feed the smoke created while cauterising tissue during surgery into amass spectrometer (MS) which will provide near-instant feedback on the condition of that tissue. “Surgeons use hot knives to
seal blood vessels and, when doing keyhole surgery in particular, there’s a lot of smoke so we use extraction pipes,” says Nicholson. By feeding the smoke into a MS, “we would use it to tell if it’s good tissue or cancerous, for example”. By using the MS (“basically a
very expensive weighingmachine that can give us weights down to seven decimal places,” says Nicholson), the information on a patient’s condition can be relayed quickly to the surgeon to enable more effective and less risky
decisions about how the procedure should progress. To help develop this technique,
Imperial College has partnered with Waters Corporation,makers of a range of analytical laboratory instruments for scientific research. Dr Robert Plumb, senior
businessmanager – pharmaceutical business operations, explains the benefits of mass spectroscopy in this application. “It provides an extremely sensitive way of detecting components and it does that extremely quickly. It creates a spectral fingerprint of the compounds that are entering the instrument at that time through analysing themolecularmass-to- charge information of the compounds.” This detailed information on the
sample, down tomolecular level, is gained by first ionising the sample, achieved by electrically charging
itsmolecules. The sample is then subjected to a combination of magnetic and electric fields which allowsmass-to-charge ratio to be determined. This provides sufficient information to characterise eachmolecule and build up a profile of what it is. Plumb adds that the high level
of sensitivity and accuracy achieved with MS is essential for this application as the difference at amolecular level, between, for example, cancerous and non- cancerous tissue is subtle. Waters’ staff in Manchester are
working with Nicholson’s teamto find the right type of MS for this task. “They’re travelling back and forth to London with samples. We have several different types of mass spectrometer and they each work in slightly different ways so we’re working with those researchers, looking at what’s suitable,” says Plumb.
could be in full operation by the year’s end. “Much will depend on howmany samples they can get through in the hospital. As long as they can get a few hundred samples passing through for each type of statistical model to be developed, it all should work. Themodels will get better asmore samples go through, as the process is self learning. That’s the beauty of it,” says Spraul. Both Spraul and Nicholsonmention that
these techniques were proven in metabonomics laboratories over a decade ago, butmore work is required. “The demands placed in terms of processing are massive. The combination of high throughput, validation and accuracymakes this very challenging work. It’s a huge cliff to climb,” says Nicholson. ■
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