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”

A4I is back for another round!

Analysis for Innovators is back! The latest round of the A4I programme from Innovate UK and its partners (LGC, NPL, NEL, & STFC) has now opened, with up to £3M available in total for Round 3.

In our role as the National Measurement Laboratory, we have worked with Innovate UK since the very start of A4I, back in January 2017, and the programme has proved such a success that we are already moving on to the third round!

But be quick to take advantage of this opportunity as the first stage of the application closes at noon on 6th September.  A4I is a very unique programme from Innovate UK – it helps UK businesses address difficult problems that restrict their potential productivity and competitiveness.  The scope is very wide (chemical, physical, biological and computing) but the problems must be of a measurement or analysis nature.

A4I targets real industry problems that haven’t been solved with existing products or services. As such, it is of interest to companies that have not traditionally considered applying for funding. Any size of business, with any type of measurement or analysis problem, are eligible to apply. If your company makes it past the first stage, you will be matched with us, NPL, NEL or STFC for a consultation. After this stage, some companies will continue to work with us in our own world-class measurement labs.

The first two rounds of the A4I programme have seen us help several companies overcome measurement problems. In Round 1, we worked with the Coconut Collaborative, a manufacturer of coconut yoghurt, and STFC to develop a rapid and robust screening method to detect rancid coconut cream before its use. The use of rancid cream led to lost sales and waste for the company. We helped develop a novel screening approach with multi-spectral imaging, which will help the Coconut Collective avoid annual costs of £500k.

We also worked with Sistemic to help ensure the safety of cell therapy products, by increasing the sensitivity of their novel technology, which detects contamination in cell therapy products. Cell therapies are seen as the future of treatment in a number of areas including diabetes and cardiovascular disease. However, one type of cell being used to generate cell therapy products (pluripotent stem cells, or PSCs) has the potential to form tumours. The NML enhanced the sensitivity and specificity of the Sistemic novel prototype miRNA-assay to the levels required for market (<10 cells per million). This assay will ensure producers can accurately assess PSC contamination in their cell therapy products.

Other examples of the companies that were funded under A4I Round 1 can be found at Analysis for Innovators winning projects, and for more information about the work and case studies of the NML at LGC, have a look here at our latest annual review.

And don’t forget to apply now– there’s £3 million up for grabs!

What’s funny about your honey?

Ensuring the safety and authenticity of the food we eat is of paramount importance and there is growing concern, both at the EU and global level, to ensure the quality control of food to protect the health and safety of consumers. And during the National Measurement Laboratory’s thirty years, we’ve done a lot of work to support reliable measurements in food testing and authentication.

Honey is known to have multiple health and nutritional benefits and is in high demand among consumers. It is defined as the natural sweet substance produced by bees and there is significant regulation around the composition and labelling of honey in order to protect consumers from food fraud. However, due to the declining numbers of bees, the impact of weather conditions on supply and the high costs production, honey is expensive. This makes it a prime target for economically-motivated food fraud.

StockSnap_97LJAKWL36Some research suggests that humans began to hunt for honey 8,000 years ago, and the oldest known honey remains, dating back to between 4,700 – 5,500 years ago, were discovered in clay vessels inside of a tomb in the country of Georgia.

The ancient Egyptians used honey to sweeten dishes and to embalm the dead, while the ancient Greeks actually practised beekeeping so much that laws were passed about it. Honey was prevalent around the ancient world, being used in ancient India, China, Rome and even among the Mayans. It even plays a role in many religions, representing the food of Zeus, an elixir of immortality, and a healing substance.

And just like any other important product, fraudsters have been faking it since it’s been in use. Ancient Greeks and Romans both mention honey adulteration, and back in 1889, Dr Harvey W. Wiley testified in front of Congress that it was the most adulterated product in the U.S.

Honey is still one of the most adulterated food products globally, with a report last year citing that more than 14% of tested samples were adulterated.

There are two types of food fraud associated with honey: adulteration and fraudulent labelling. Honey adulteration typically occurs by substituting honey for cheaper sweeteners such as high fructose corn syrup, cane or beet sugar syrup. Fraudulent labelling occurs because honeys from a particular geographic or botanical source, such as Manuka, command premium prices amongst consumers.

Detecting these types of fraud presents a significant measurement challenge for food regulators: adulterated products show very similar physical and chemical properties to pure honey and mis-labelled products are, in fact, pure honey, just of lower quality. Several reports indicate that there is more Manuka honey being sold than Manuka bees can  produce, which illustrates how often lower quality honeys are passed for premium ones in order to maximise profit.

During our thirty years as the National Measurement Laboratory (NML) for chemical and bio-measurement, our scientists have conducted several reviews and studies of methods for detecting honey fraud1. For instance, nearly forty years ago, scientists began to use stable carbon isotope ratio mass spectrometry (IR-MS) to detect high fructose corn syrup in honey.  As our scientists found2, it is possible to identify food fraud in honey using IR-MS, which measures small but observable variations in the ratios of the two stable isotopes of carbon (C-13 and C-12). Sugars, although chemically identical, have a different isotopic signature depending on the way in which the plant processes carbon dioxide. As the majority of honey-source plants use a different pathway than plant sugars typically used as honey adulterants, it is possible to detect adulteration using IR-MS. The specific geography of the plants also plays a role in the isotopic fingerprint and IR-MS can be used to determine where honeys originated.

However, in order that these types of measurements are robust and reliable in detecting food fraud across the supply chain the comparability of results is critical. To support this, LGC co-ordinated an international comparison study in 2016 for isotope ratios in honey involving 6 national measurement institutes (NMIs) and 6 expert laboratories (contacted via the Forensic Isotope Ratio Mass Spectrometry (FIRMS) Network) and the results between participants showed good comparability.

Demonstrating the comparability of isotope ratio measurements is crucial to detecting many types of food fraud and supporting food authenticity claims, of which honey is just one example. The international study coordinated by LGC demonstrates the measurement framework is in place to support food fraud regulation in the future.

 

1 D. Thorburn Burns, Anne Dillon, John Warren, and Michael J. Walker, 2018, A Critical Review of the Factors Available for the Identification and Determination of Mānuka Honey, Food Analytical Methods, https://doi.org/10.1007/s12161-018-1154-9.

2 Helena Hernandez, “Detection of adulteration of honey: Application of continuous-flow IRMS”, VAM Bulletin, 1999, Vol 18, pp 12-14.

The National Measurement Laboratory turns 30!

In 1988, Government Chemist Alex Williams, seeing the need for improved quality of analytical measurements, initiated and launched the Valid Analytical Measurement (VAM) programme to develop a chemical measurement infrastructure in the UK.

This programme would go on to evolve into the National Measurement Laboratory for chemical and bio-measurement. The UK was one of the pioneers within the global measurement community to recognise the need to address the new and developing challenges of measurement across chemistry and biology.

An article from the early VAM bulletins (1989).

That means 2018 marks the NML’s 30th birthday and kicks off our ‘Year of Measurement’. It is an opportunity to celebrate the importance of measurement science (‘metrology’) as we enjoy our 30th birthday and join the upcoming Festival of Measurement, which launches in September and lasts through May 2019.

In our thirty year history of performing measurements to support the UK, we’ve experienced a lot of growth, seen big changes in the challenges we’ve been set and made some major breakthroughs. We’ve asked (and answered) a lot of questions, like ‘What are the best methods for the detecting the adulteration of honey’ or ‘Is the computer a friend or foe?’ (The answer is ‘friend’…or ‘both’ if you’ve invested heavily in encyclopaedias.)

We’ve already outlined in a recent blog post how important accurate measurement is, affecting everything from food and drink to medicine. Accurate and precise measurement is the foundation of public health and safety. But it’s also just as important to the economy.  In 2009, it was estimated that £622 billion of the UK’s total trade relied on measurement in some way, meaning that measurement plays a role in nearly every aspect of our lives.

Our Chief Scientific Officer, Derek Craston, agrees that good measurement is crucial to economies. ““In my role, I am fortunate to be able to see the major benefits that chemical and biological measurements make to the prosperity of companies and the lives of individuals across areas as broad as clinical diagnosis, drug development, environmental protection and food security. Indeed, in a global economy, with complex supply chains and regulatory frameworks, it is hard to see how many markets could function without it.”

We’re proud of the work we’ve done as the National Measurement Laboratory, where our work supports manufacture and trade, protects consumers and enhances quality of life. And over the next few months, we plan to share stories and case studies from our thirty years at the forefront of measurement with you, as well as look forward to the next thirty years.

Delivering impact to support AIDS research

LGC is helping to ensure that research into a cure for HIV is based on sound fundamental measurements.

Over 36 million people currently live with HIV, with approximately 2 million becoming infected each year (WHO 2015). Although HIV can be successfully managed with combination antiretroviral therapy (cART), the therapy must be continued indefinitely as no cure presently exists. This can be challenging in regions with high HIV prevalence and long-term use can potentially have toxic side effects.

One barrier to curing HIV is the presence of infected host cells that are not targeted by current therapies but lay dormant (so-called ‘viral reservoir’). These cells have the potential to become re-activated so novel strategies to cure HIV aim to target this reservoir. To determine whether these new approaches are successful, accurate and robust, methods for measuring HIV DNA are required.

The Molecular and Cell Biology team at LGC perform research to support accurate and reliable measurement as part of our National Measurement Laboratory (NML) role. Recent work by NML scientists comparing different molecular methods (qPCR, digital PCR) for quantification of HIV DNA has raised some concerns around the current popular choice of calibrator used to compare results between HIV clinical studies (8E5, ATCC® CRL-8993). It appears to lose HIV DNA copies during cell growth, potentially producing misleading estimates of how much HIV DNA is present and affecting whether novel strategies towards curing HIV are deemed successful or not.

Based in part on our work, the NIH AIDS Reagent Program, which provides critical reagents and resources to support research in the areas of AIDS therapeutics and vaccine development, has recently highlighted the potential instability of the standard on its reagent database to support the research community and enable the best chances of success.

 

 

Citation:

Busby E et al. Instability of 8E5 calibration standard revealed by digital PCR risks inaccurate quantification of HIV DNA in clinical samples by qPCR (2017) Sci Rep 7(1):1209. doi:10.1038/s41598-017-01221-5

Finding harmony in newborn blood spot screening

Every forty seconds, a baby is born in the UK. That’s nearly 775,000 births across the United Kingdom in 2016 alone. It’s important that each of these children is given their best chance at a healthy future from the moment they are born.

Currently, all parents of newborns in the UK are offered newborn blood spot screening, a test which detects nine conditions and inherited diseases, including cystic fibrosis, congenital hypothyroidism, and sickle cell disease. The level of hormones or amino acids in the blood at the time the sample is taken leads to early detection. The goal is to detect and treat conditions before they cause severe developmental problems or unnecessary suffering so children can lead as normal lives as possible.

With the number of infants tested each year and the use of nationally agreed protocols with specified cut-off values, harmonisation of methods across the 14 laboratories performing these tests is extremely vital.  Each time a sample is analysed, it should produce the same results. The cost and time of retesting samples can be great and can cause unnecessary stress to the families at an already challenging time.  Additionally, the network of newborn screening laboratories in the UK should have access to the newest, most accurate methods and data.

This is why we have partnered with Dr Rachel Carling, one of the country’s foremost authorities on newborn screening, and the NHS England as part of the CSO’s Knowledge Transfer Partnership (KTP), a programme that teams up leaders in healthcare with the UK National Measurement System’s lab, including the National Measurement Laboratory (NML) at LGC, to solve measurement challenges in their fields.

Through the partnership, we plan to help create methods and materials that will lead to greater harmonisation and provide a framework within which more analytes can be added to the UK’s screening programme to be able to test for new diseases at birth.

As part of the KTP, LGC’s Chris Hopley and Simon Cowen will be discussing best practice in newborn screening with the network of labs at a workshop in London this week. Together, we hope to help deliver greater efficiency and certainty for these children and their families.

Analysis for Innovators: How we can solve your measurement problem

LGC, in our role as the UK National Measurement Laboratory and Designated Institute for chemical and bio-measurement, partnered with Innovate UK to launch a new funding programme ‘Analysis for Innovators’ (A4I) last year.

The aim of A4I was simple: to solve real problems affecting productivity or performance of UK companies of all sizes using the world-leading measurement facilities available at LGC and other national laboratories (NPL, NEL, STFC).

After the success of the first round, Analysis for Innovators is opening a new round of applications in March to UK companies who wish to take advantage of our expertise, research and development to help solve a measurement problem. And this year’s round has £4 million reserved to fund 12-month projects, with up to £250,000 for each project.

Companies are asked to submit a two-minute video outlining an existing measurement problem, without providing any solutions. This gives us insight in to what the obstacle looks like, the approaches the companies have already tried, and how solving it might change their business going forward.

After watching the videos from last year’s competition, LGC scientists sat down with the competition winners and discussed the problems in more detail. This approach encouraged creative thinking from our scientists and provided companies with access to our experts even if they did not progress to the next competition stage. In fact, feedback from the first round indicated that this stage was itself incredibly useful, and as a result the initial successful outcome of the current A4I programme will be a longer consultancy session with our measurement experts before progressing on to potential projects.

Previous collaborations included developing an assay to continuously monitor cortisol for a wearable device to improve diagnosis and treatment of disease, improving the sensitivity of a novel assay developed to ensure the safety of cell therapy products, and optimising an innovative non-chemical disinfection process to provide a cost-effective system for cleaning water and other fluids.

This programme benefits companies who otherwise would not be able to consult with our scientists, but it also benefits LGC by giving us the opportunity to see the outcomes of the vital measurement work we do every day. Our scientists are at the forefront of measurement technology, so it’s exciting to see how our science can affect and change lives for the better. These applications of our expertise remind us why what we do is important and inspire us to continue.

If you’re planning on applying for the next round of funding, or if you’d just like to learn more about the programme, register to join us at one of the remaining roadshows in February and March. We’ll be there to help share the work of our collaborations and illustrate how our analysis can help solve your problem.