Every DNA counts – and we would know

The National Measurement Laboratory at LGC turned 30 years old this year, and to celebrate we’ve been looking back at notable accomplishments, and looking at where we are now. Clinical measurement is one field where our scientists have excelled and innovated throughout our time.

biology-clinic-doctor-4154Clinical measurement “is the development, use, on-going support, and maintenance of technology for diagnosing, aiding or treating patients.” Modern medicine wouldn’t be possible if we couldn’t rely on the accuracy of clinical tests and diagnosis. Poor measurement can lead to misdiagnosis, incorrect prescription and dosage of medicine, or false interpretation of data. Therefore, reliable certified reference materials are absolutely necessary to ensure the quality and accuracy of clinical measurement.

Throughout the last 30 years, the National Measurement Laboratory (NML) at LGC has worked in this area to ensure that testing methods and reference materials are of the highest quality.

In one case study from 2006¹, scientists in the NML developed isotope dilution liquid chromatography-mass spectrometry (IDMS) methodologies that were then used to generate reference values for clinical reference materials (CRM), some of which led to the analysis of creatine in frozen serum and testosterone in frozen serum CRMs.

In another blog post, we outlined the work we’ve done to improve Alzheimer’s diagnosis, which could lead to techniques for earlier diagnosis of the disease, and in another, we illustrate the importance of harmonising newborn blood sport screening tests to ensure infants are diagnosed and treated early so that they can live as normal lives as possible.

An important part of working in the field of clinical medicine and measurement is communicating our knowledge with other scientists and medical professionals to ensure that good measurement is being performed consistently across the board. We have worked with the NHS and England’s Chief Scientific Officer Sue Hill on doing just that as part of the Knowledge Transfer Partnership Programme, which aims to improve patient care through new approaches to measurement.

And now, our scientists can even count DNA and measure changes to that DNA over time. Identification and targeting of specific genetic sequences forms the basis of many promising advanced healthcare solutions such as: precision (personalised) medicine in cancer, gene therapies to end genetic disorders in children and the detection of pathogenic and non-pathogenic bacteria in a wide spectrum of infectious and autoimmune diseases.

However, the new methods and technologies currently being developed will only achieve their full potential if we can ensure they are safe and can be reproduced. High accuracy reference methods are one of the key factors in supporting their development into routine application.

Using tests for guiding treatment of colorectal cancer as a model, our scienists outlined in a paper published in Clinical Chemistry how a range of dPCR assays and platforms compared and how precisely they measured the cancer mutation. An inter-laboratory study of clinical and National Measurement Institute laboratories demonstrated reproducibility of the selected method. Together these results reveal the unprecedented accuracy of dPCR for copy number concentration of a frequently occurring gene mutation used to decide on drug treatment.

This study has shown that using high-accuracy dPCR measurements can support the traceable standardisation, translation and implementation of molecular diagnostic procedures that will advance precision medicine.

All of this just goes to show you how far we’ve come in 30 years!

¹VAM Bulletin, Issue 35, Autumn 2006, pp 13. ‘Case Study 3: IDMS certification of clinical reference materials using LC-MS/MS”

Alzheimer’s disease diagnosis: the end of the guessing game?

There are currently around 850,000 people living with dementia in the UK, and the number of people affected is expected to reach 2 million by 2051. The costs associated with dementia, estimated now at £26 billion a year, are likely to treble.

Alzheimer’s disease is the most common type of dementia, affecting between 60 and 80 percent of those diagnosed. There is no known cure, with treatments limited to preserving cognitive function. Currently, there is no non-invasive method for diagnosing Alzheimer’s disease with GP’s relying on in depth cognitive tests, with clinical confidence in diagnosis typically at 70-80%.

Doctor Helping Elderly

If confident early diagnosis could be achieved through noninvasive techniques, treatment could be introduced earlier delaying the onset of memory impairment.

The solution

The development of plaques or tangles of certain proteins (β-amyloid and tau proteins) in the brain is a known feature in Alzheimer’s disease. It is also known that abnormal accumulation of metals underlies several neurodegenerative diseases. Iron, in particular, is associated with the formation of neurofibrillary tangles in the β-amyloid plaques. The recent advances in the use of Magnetic Resonance Imaging (MRI) for the earlier detection of neurological diseases require validation to ensure the integrity of the images obtained is adequate for diagnostic purposes.

Researchers at LGC, in collaboration with partners, have been working to establish a link between novel MRI scans and quantitative elemental mapping of soft tissues. A method of mapping the levels of iron in sections of the brain using laser ablation (LA) coupled to Inductively Coupled Plasma Mass Spectrometry (ICP-MS) has been developed, along with a novel calibration strategy and standard to support quantitative tissue imaging. Correlation of the metal content associated with β-amyloid protein and MRI images will help diagnosis of AD at an early stage, where preventative therapy will have greater impact.

LGC has developed a novel calibration strategy for LA-ICP-MS that produced quantitative images for iron in whole mouse brain sections (provided through collaboration with Kings College London and the University of Warwick) and compared them with results from micro x-ray fluorescence (μ-XRF) (provided through collaboration with Ghent University and the University of Warwick). The data showed good agreement in total iron concentrations for a selection of areas within the mouse brain sections. This finding supports the proposed method as a quantitative approach; the calibration strategy has been published in the Journal of Analytical Atomic Spectrometry¹.

Impact

The development of this method for quantitative imaging of iron in the brain has the potential to lead to techniques for earlier diagnosis of Alzheimer’s disease, enabling earlier intervention, therapies and treatment aimed at delaying the onset of symptoms.

Delaying the onset of neurodegenerative disorders, such as Alzheimer’s disease, by five years could halve the number of deaths from the condition, saving 30,000 lives a year and billions of pounds in treatment costs. Reducing severe cognitive impairment in the elderly by 1% pa would cancel all estimated increases in long-term care costs due to our ageing population.

The methodology will also provide deeper understanding of the early development of Alzheimer’s disease leading the way for new treatments aimed at preventing the disease.

Heidi Goenaga-Infante, Principal Scientist for inorganic analysis at LGC, commented: “This cutting-edge research is already proving to be of significant benefit to the validation of non-invasive diagnostic tools for Alzheimer’s disease. The potential for metal imaging mass spectrometry of other biological tissues to probe the reported links between metals and disease states is now a step closer.”

If you’d like to learn more about our work and read other case studies, visit our website.

¹ J O’Reilly, D Douglas, J Braybrook, P.-W. So, E Vergucht, J Garrevoet, B Vekemans, L Vinczec and H Goenaga-Infante, “A novel calibration strategy for the quantitative imaging of iron in biological tissues by LA-ICP-MS using matrix-matched standards and internal standardisation”, J Anal. At. Spectrom., 2014, 29, 1378-1384