NMR and metabolic phenotyping

In this interview, Dr Harmut Schafer introduces the work being done at the Phenome Center in Birmingham, on metabolic phenotyping using NMR.

Please can you give an overview of the Phenome Center Birmingham?

The Phenome Center Birmingham is a large, state-of-the-art, £8M metabolic phenotyping facility that has been established as part of a stratified medicine initiative led by the Medical Research Council.

It is mainly located in the School of Biosciences, the College of Life and Environmental Sciences and the Henry Wellcome Building for biomolecular nuclear magnetic resonance (NMR) spectroscopy at the University of Birmingham.

The center provides a collaborative environment where metabolic phenotyping of the human population can be performed in medical research and stratified medicine.

Experts from different fields including experimental design, statistics, bioinformatics and analytical chemistry will conduct small- and large-scale studies in human and model organisms to improve understanding of human diseases, identify targets for nutritional, exercise or drug interventions and provide strategies for prognosis, diagnosis and treatment in stratified medicine.

Two 600 MHz NMR spectrometers will be used at the center, along with eleven ultra-high performance liquid chromatography-mass spectrometers coupled with automated liquid handling robotics and a sophisticated computational infrastructure. It is possible to analyze more than 30,000 samples per year at the Phenome Center Birmingham.

What is metabolic phenotyping?

Metabolic phenotyping is an approach that looks at the molecular relationships between the genotype, lifestyle and the environment. The whole collection of metabolites in the human body, which is made up of more than 40,000, is referred to as the metabolome. This metabolome is divided into tissue-specific or biofluid-specific metabolomes. The blood metabolome for example has a different metabolomic profile to the urine metabolome.

The genome provides instructions for the formation of structures and biochemicals in the body. It remains relatively constant throughout a person’s lifetime, with only small changes occurring as a result of mutations or single nucleotide polymorphisms.

In contrast, the metabolome is very dynamic, constantly and quickly responding to changes in the environment. If you exercised, for example, your muscle and blood metabolomes would be different after the exercise to how they were before the exercise. This sensitivity the metabolome has to lifestyle changes and environmental stimuli can be used to understand disease mechanisms and to establish metabolic markers that can be applied in the prognosis, diagnosis and treatment of disease.

What Bruker systems are available at the Phenome Center in Birmingham?

The center has two of Bruker’s NMR AVANCE-IVDr systems, which are specified according to our IVDr specification. This IVDr specification is standardized with respect to the magnetic field, which is a 600-megahertz system.

The AVANCE-IVDr system, developed by Bruker represents a complete, proven and standardized platform for NMR clinical screening, as well as for IVD-by-NMR research. It comes with a specific sample changer or so-called SampleJet and it has a room temperature probe.

In terms of NMR technology, the system set-up is very simple and so you do not need an NMR spectroscopist to run it. The system set-up is such that even a medical technical assistant could run it. This is possible, not just because of the hardware, but because of the additional software Bruker provide.

At Bruker we have several layers in the software. One layer, which is particularly important at the Phenome Center, is an automation layer, which enables a very easy set-up of sample sets to be run by the NMR system. So far, it is a press-button solution, which with standard protocol, can run around 100 to 120 samples per day if you are using urine samples; or 60 to 80 samples if you are using plasma and serum samples. This is a standardized protocol.

You can go much higher if you want, if you have particular applications, depending on your particular objectives. As a result of a long-term collaboration between Bruker and Imperial College London, the AVANCE-IVDr platform already enables more than 100,000 samples to be analyzed every year at the National Phenome Center that was opened at Imperial College in 2013.

How will the NMR and mass spectrometry facilities available impact metabolomics research?

Migrating from translational research to clinical diagnostics requires robust, identical instrumentation in research facilities and hospitals, which is why Bruker has decided to offer the standardized IVDr by NMR platform. It enables a smooth transfer from health research and large epidemiological studies, to their partners’ emerging IVD assays at the highest quality and reproducibility.

With modern NMR technology and the right standard operating procedures (SOPs), Bruker and their collaborators have opened the path to complex mixture analysis using push-button technology, establishing NMR as one of the two major technologies used in metabolic profiling and screening.

What impact will the NMR spectrometers have on the metabolic phenotyping at the center in Birmingham?

The system basically puts this particular lab into the global network of phenome centers, which means that whatever is produced here in terms of data is completely comparable with data generated, for example, in the phenome center in London or other areas. That means you are able to pool data with all partners sitting on the same protocol and the same instrument.

That is basically valid, so to say, over the next decades, as long as those protocols are applied. Bruker-validated SOPs ensure that clinical data is highly reproducible, allowing labs across the world to exchange and validate novel NMR assays. In this context, Bruker is the NMR partner in the growing global network of phenome centers.

You have to consider that studies are getting larger and larger, so we're talking really about large-scale and long-term studies, which would mean that many of them cannot be run by a single lab anymore. Data pooling, data sharing and respective model sharing is a vital part of the phenome center concept. Here at this phenome, this lab is now integrated into this concept and is basically one operation they have in this network.

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